Journal of Controlled Release 268 (2017) 364–389

Contents lists available at ScienceDirect

Journal of Controlled Release

journal homepage: www.elsevier.com/locate/jconrel

Review article

Progress in brain targeting drug delivery system by nasal route MARK

⁎
Abdur Rauf Khan, Mengrui Liu, Muhammad Wasim Khan, Guangxi Zhai
Department of Pharmaceutics, College of Pharmacy, Shandong University, 44 Wenhua Xilu, Jinan 250012, China

A R T I C L E I N F O A B S T R A C T

Keywords: The blood–brain barrier (BBB) restricts the transport of potential therapeutic moieties to the brain. Direct tar-
Blood-brain barrier geting the brain via olfactory and trigeminal neural pathways by passing the BBB has gained an important
Intranasal delivery consideration for delivery of wide range of therapeutics to brain. Intranasal route of transportation directly
Nanoparticles delivers the drugs to brain without systemic absorption, thus avoiding the side effects and enhancing the efficacy
Liposomes
of neurotherapeutics. Over the last several decades, different drug delivery systems (DDSs) have been studied for
Polymeric micelles
targeting the brain by the nasal route. Novel DDSs such as nanoparticles (NPs), liposomes and polymeric micelles
have gained potential as useful tools for targeting the brain without toxicity in nasal mucosa and central nervous
system (CNS). Complex geometry of the nasal cavity presented a big challenge to effective delivery of drugs
beyond the nasal valve. Recently, pharmaceutical firms utilized latest and emerging nasal drug delivery tech-
nologies to overcome these barriers. This review aims to describe the latest development of brain targeted DDSs
via nasal administration.
Chemical compounds studied in this article: Carbopol 934p (PubChem CID: 6581)
Carboxy methylcellulose (PubChem CID: 24748)
Penetratin (PubChem CID: 101111470)
Poly lactic-co-glycolic acid (PubChem CID: 23111554)
Tween 80 (PubChem CID: 5284448)

1. Introduction
Despite of the tremendous advancement in drug delivery systems
(DDSs) for treatment of central nervous system disorders like schizo-
phrenia, migraine, Parkinson's, Alzheimer's disease and brain tumors,
still there is need of novel brain targeted DDSs. The major hurdle for
targeting the drug to brain is the presence of BBB. BBB is the delicate
network of blood vessels having tightly packed endothelial cells which
separates the brain from circulatory system. It protects brain from entry
of harmful substances such as toxin and bacteria. Hydrophilic sub-
stances, charged molecules, proteins and peptides are unable to cross
this barrier, whereas lipophillic drugs such as antidepressants, anxio-
lytics and many hormones can easily cross the endothelial cells [1].
Patients suffering from neurological disorders required chronic dosing,
leading to side effects in non targeted organs. It is considered that
majority of drugs which are useful to treat the neurological disorders
have lost their potential due to the BBB, resulting in limited treatment
options for the patients suffering from neurodegenerative diseases and
brain cancer [2]. Therefore, non-invasive transport of drug to brain is
highly needed for neurological disorders and brain tumors requiring
chronic therapy. Olfactory pathway is a reliable alternative to achieve
desire therapeutic effects at lower doses for treating chronic diseases
while minimizing the side effects. Transmucosal delivery of drug
through olfactory or trigeminal pathway to brain by passing the BBB is
referred as the direct IN drug transportation to brain. This is the only
route through which brain is in connection with the outside environ-
ment [3]. This neural connection has gained attention for delivery of
wide variety of drug molecules by the formulations ranging from small
molecules to large molecules such as nucleotides, peptides and proteins
to brain by preventing the enzymatic degradation and enhancing the
pharmacological effects without systemic absorption and toxicity to the
major peripheral organs. In animal and human studies, it was in-
vestigated that different DDSs by improving the nasal permeability,
increasing mucoadhesion, providing constant or controlled release of
drug or increasing deposition at olfactory epithelium resulted in suc-
cessful delivery of drug from direct nose to brain [4,5].
This review highlights literatures regarding pathways and me-
chanisms of therapeutic agents transporting across nasal mucosa and
latest developments on novel DDSs using various formulation strategies
to improve the IN drug delivery to brain. Colloidal carriers such as
various types of nanocarriers (NPs, micelles, nanogels, nanoemulsions
and liposomes) and microspheres as potential DDSs to brain are main

⁎
Corresponding author.
E-mail address: zkyjd@sdu.edu.cn (G. Zhai).

http://dx.doi.org/10.1016/j.jconrel.2017.09.001
Received 3 May 2017; Received in revised form 31 August 2017; Accepted 1 September 2017
Available online 06 September 2017
0168-3659/ © 2017 Published by Elsevier B.V.
A.R. Khan et al. Journal of Controlled Release 268 (2017) 364–389

Chemical Disruption of agents in brain [18]. Efficiency of vasoactive agents could be main-
BBB
tained by conjugating onto the surface of NPs. A study has shown that
Focus Ultrasound
Enhanced Delivery coupling of methylmethacrylate-sulfopropylmethacrylate (MMA-SPM)
Craniotomy-Based Drug NPs with RMP-7 resulted in successful delivery of antiretroviral drug
Invasive Strategies Delivery across BBB. This strategy of combining liposomes or NPs encapsulating
Convection Enhanced
Delivery
drugs with hyperosmotic agents has shown positive results in im-
Polymeric Wafers and proving drug delivery to brain and reducing systemic side effects [19].
Microchip Technology Liposomes grafted with peptidase inhibitors [20], bradykinin and eto-
Efflux Pump poside [21] promoted the transport of encapsulated drugs across BBB.
Inhibition
Prodrug Approach 2.1.2. Focus ultrasound enhanced delivery
Non Invasive The use of ultrasound waves to reversibly and transiently open the
Strategies Cell Based Therapy
Drug Delivery Strategies BBB is another versatile approach for enhancing of drug transportation
for Brain Targeting Nanocarriers as Drug
Delivery System
to the CNS [22]. Ultrasound based drug delivery utilized microbubbles
Intranasal Drug
(MBs) as a contrast agent [23,24]. These bubbles were administered
Delivery systemically and worked on acoustic energy principle to exert pressure
on endothelial cells and open the tight junctions, resulted in increased
Antibodies Mediated
Drug Delivery permeability of BBB and improved delivery of drug to the brain [25].
Recent Mfsd2a Based Drug MBs have diameter of 1–10 μm and are made of semi rigid lipid and
Advancements in Delivery albumin shells encapsulated with perfluorocarbon [26]. These MBs
Brain Targeted
Drug Delivery Facial Intradermal operate in collaboration with low intensity Focus Ultrasound (FUS) and
Injection
this combined system is called MB facilitated FUS. MB-FUS system
Laser Light decreases the acoustic energy requirement, focusing the acoustic energy
Technology
within blood vessels. Different antitumor agents such as trastuzumab
Fig. 1. Diagrametic presentation of drug delivery strategies for brain targeting. [27], temozolomide [28], methotrexate [29], neucleotides i.e. siRNA
[30] and stem cells [31] have been successfully delivered with the help
of FUS. FUS-MB system is effectively used with other DDSs for brain
focus of discussion. Patented technology based drug delivery devices for
targeted delivery. This system could be utilized in combination with
efficient nasal delivery of drugs are highlighted in this review.
PEGylated NPs to disrupt the BBB for enhanced delivery, target the
Moreover, limitations as well as future prospects of such brain targeted
cancerous cell and increase penetration [32]. FUS technique coupled
DDSs are also discussed in details.
with liposomes had shown optimum effects of doxorubicin in rat glioma
[33]. FUS grafted gold NPs guided through MRI were delivered to brain
2. Drug delivery strategies for brain targeting tumor model. FUS system could be helpful for gene therapy of brain
tumor [34]. Successful delivery of NPs encapsulating reporter gene
Various drug delivery strategies to disrupt or overcome the BBB and combined with MRI guided FUS to transfect the brain, is the clue for
potentiate the transport of drug molecules across this barrier to the CNS future prospects of this technology for gene therapy [35].
have been studied. These strategies are divided into three main cate- High-Intensity Focused Ultrasound (HIFU) is effectively applied for
gories; invasive and non invasive strategies and recent techniques for reversible disturbance of BBB and promotion of drug distribution to the
BBB disruption (Fig. 1). brain in a précised and controlled way without toxicity to brain par-
enchyma tissues. This technique is valuable for tumor targeted delivery
2.1. Invasive strategies of drugs, genes and antibodies [36–38]. Interstitial fluid pressure lim-
ited the distribution of NPs to the tumor. HFU increased the perme-
2.1.1. Chemical disruption of BBB ability of endothelial cells and NPs were moved from leaky endothelial
Numerous invasive techniques are used to disrupt the BBB and en- cells to the tumor microenvironment resulting in improved distribution
hance the delivery of drug to brain. Osmotic disruption of BBB is one of of anticancer agents to the tumor targeted area.
the invasive techniques involving temporarily shrinkage of endothelial
cells, opening of tight junctions and leakage of drug to the CNS [6–8]. 2.1.3. Craniotomy-based drug delivery
On injecting intracarotid hypotonic solution of mannitol, tight junctions Craniotomy-based drug delivery is the direct way of targeting the
were opened and subsequently promoted the delivery of chemother- specific part of the brain without exposure to peripheral organs via
apeutic agents to the brain. Osmotic disruption enhanced 2.5–7.6 fold Intracerebral or intraventricular injection. In intraventricular delivery,
transport of methotrexate, aminoisobutyric acid and dextran 70 to CNS drug reservoir implanted in the scalp provided the controlled release of
[9]. This technique is less specific and inefficient and major drawbacks a drug and is connected to the ventricles in the brain through catheter
are transport of plasma protein to CNS, disturbed glucose uptake, mi- [39,40]. Higher concentration of drugs is achieved without distribution
croembolism, neurotoxicity of cerebral tissues, altered brain functions to the interstitial fluid of brain. Intraventricular system directly delivers
and technicality related issues. the drug to the ventricles and subarachnoidal part of the brain and is
Vasoactive agents such as bradykinin and histamine disturb the BBB suitable for therapy of meningioma and metastatic cells of CSF [41].
and improve the transportation of drugs to CNS [10–12]. Purpose me- Intracerebral system directly injects or infuses the drug into brain
chanisms involved in BBB opening effects of bradykinin are the acti- parenchyma through catheter [42] and controlled devices maintain the
vation of B2 receptors, leakage of endothelial cells based on modulation delivery [43]. This system depends on the diffusion mechanism and
of caveolin-1 and caveolin-2 [13] and permeability enhancement of provides slow distribution of drugs within the brain, as diffusion de-
brain tumor microvessels via (KATP) channels [14]. In preliminary creases with the increase of distance. Hence, intracerebral delivery re-
clinical trials, intra arterial infusion of RMP-7, agonist of bradykinin, quires large doses of a drug to achieve desired therapeutic response
resulted in 2.7 fold enhanced transport of carboplatin [15] but phase II [44].
and III clinical trials had shown inefficiency of RMP-7 in the treatment
of glioma [16,17]. The Transient effect and unevenly distribution of 2.1.4. Convection-enhanced delivery (CED)
receptors in the brain led to the poor distribution of chemotherapeutic Convection-enhanced delivery (CED) overcomes the disadvantages

365
A.R. Khan et al.
of intracereberal delivery system. This diffusion system utilizes con-
tinuous infusion method and pressure gradient to distribute large vo-
lume of drugs at target tissues via intracranial catheter. CED has certain
limitations of drug exposure to surrounding tissue, difficulty in de-
signing the optimum formulations, instability of drug and sub-
therapeutic level of drug in the target area [45–47]. Coupling of CED
with liposomes improved the efficiency of CED for brain tumor tar-
geting. PEGylated liposomes encapsulating temozolomide (TMZ) were
studied on rat bearing glioblastoma multiforme (GBM). Liposomal de-
livery, significantly, inhibited tumor volume and increased the survival
rate [48]. CED process was further improved using efflux-resistant in-
fusion cannula to increase the infusion rate and liposomal delivery was
guided through MRI [49]. PLGA NPs based on CED technology were
investigated in animals bearing intracranial tumor for targeted and
controlled delivery. NPs distribution was comparable to that of healthy
animals but distribution to surrounding tissues was observed [50].
2.1.5. Polymeric wafers and microchip technology
Advancement in polymer technology led to development of poly-
meric devices for targeted and controlled delivery of therapeutic moi-
eties. Circumventing the BBB and providing the controlled release of
drug at intracranial tumor using polymer devices, is a big achievement
in the field of polymer nanotechnology. Wafers based on polyanhydride
were implanted in tumor resection area, crossed the BBB, gradually
released and distributed the drug into the brain and targeted site [51].
Gliadel® is effective for chemotherapy of recurrent and newly diag-
nosed glioblastoma followed by radiotherapy. FDA approved Gliadel®
as adjunct to surgery for recurrent glioblastoma patients and radiation
and surgery for high grade malignant glioma patients [52,53]. Phase III
clinical trials based on combination therapy of Gliadel®, radiation and
oral temozolomide increased median survival time upto 2 months [54].
Polymeric wafer was the first clinically used local strategy to cross BBB
and provided sustained release of carmustine at the tumor targeted site.
Clinical studies have proved useful potential of Gliadel® in newly di-
agnosed glioblastomas. Gliadel® wafers have gained importance in
saving the therapeutic potential of drugs that lost their efficiency due to
systemic toxicity or BBB impermeability. Camptothecin failed in clin-
ical trials due to systemic side effects. Local delivery based on poly-
anhydride polymers had shown efficacious results in animals without
major organ toxicity [55]. Wafers have certain limitations of less pe-
netration into deep brain tissue, cyst formation, meningitis, impaired
wound healing and abscess formation.
Programmable microchips are intracranial devices implanted to
control the release of drug at targeted site. Two types of chips are mi-
croelectromechanical systems (MEMS) and the passive chip. Single and
multiple doses could be delivered through chip technology. Active
microchips based on MEMS comprise drug filled reservoir on silicon
chip and provide highly programmable release of drug at the targeted
site [56]. Active chip technology enabled development of multiple re-
servoirs containing separate drugs to be released at the same or dif-
ferent required time intervals. Passive chips release the drug on gradual
degradation of polymeric film surrounding microreservoir. These chips
also deliver multiple drugs on demand of the therapy. These active and
passive devices offer several advantages over polymeric drug delivery.
Higher drug loading, drug remained in contact with microchip, no in-
teraction of drug with polymer and programmed controlled release of
drug made these devices superior to polymer delivery [57]. Preclinical
studies of temozolomide and carmustine using MEMS and the passive
chip were conducted in rodent gliosarcoma model. Device effectively
delivered the drug and increased survival time in 9 L glioma model
[58]. In another study, chemotherapeutic effect of 1,3-bis (2-chlor-
oethyl)-1-nitrosourea (BCNU) on Fischer gliosarcoma rat model using
passive microchip device was investigated. BCNU effectively reduced
the tumor volume compared to empty device [59].
366
Journal of Controlled Release 268 (2017) 364–389
2.2. Non-invasive strategies
Non invasive approaches exploit the endogenous mechanisms for
transport of drug across the BBB. These strategies include prodrug ap-
proach, chemical modulation of BBB, efflux pump inhibition, alter-
native route of administration and nanocarriers based drug delivery to
the brain.
2.2.1. Efflux pump inhibition
Another barrier for effective drug transportation to the brain is the
presence of efflux pump in the BBB. Efflux by the active P-glycoprotein
(P-gp) presents on the apical membrane of the endothelial cells of BBB
results in poor drug availability at the targeted brain tissues. P-gp has
more association with lipophillic and cationic drugs [60]. Most of the
low molecular weight drugs such as nitrosoureas are substrate for P-gp
and are restricted to enter the brain. Inhibition of P-gp efflux is the
useful approach to save the therapeutic efficacy of potent drugs. Pa-
zopanib is candidate for P-gp efflux. Administration with elacridar, P-gp
inhibitors, significantly enhanced the brain uptake of pazopanib [61].
First generation P-gp inhibitors, verapamil and cyclosporine A, asso-
ciated with cytochrome P450 3A (CYP3A) enzymes inhibitions and are
toxic. Valspodar is second-generation strong P-gp inhibitor with less
toxicity related issues. Elacridar, zosuquidar, and tariquidar are third
generation inhibitors with proved safety and have no effect on CYP3A
enzymes inhibitions [62,63]. To avoid serious side effects associated
with efflux inhibitors, dual therapy of efflux inhibitors with NPs was
explored. Verapamil was delivered in combination with paclitaxel mi-
celles to investigate paclitaxel toxicity in multi drug resistant (MDR)
cancer cells. Combination therapy exhibited toxicity of paclitaxel in
MDR tumor cells [64]. Patil et al. conducted a study and reported that
paclitaxel encapsulated NPs were unable to exhibit antitumor effect on
drug resistant tumor model. NPs encapsulated with tariquidar and pa-
clitaxel had shown antitumor effect on mouse model [65]. In vitro
studies of PEGylated liposomes encapsulated with Ariquidar/paclitaxel
and PEG-PE micelles containing elacridar-/paclitaxel revealed positive
results [66,67].
In addition to P-gp, multidrug resistance-associated protein (MRP)
family located on the endothelial cells involved in the efflux of cationic
molecules. MRP is responsible for multi drug resistance of cancer to
chemotherapeutic agents. The basic function of P-gp and MRP is to
protect the brain from entry of harmful chemical substances resultantly
inhibit the entry of drugs to the brain. Inhibition of P-gp and MRP si-
multaneously could be beneficial for brain targeted delivery [68].
2.2.2. Prodrug approach
Increasing the lipophilic characteristics of a drug facilitates the BBB
permeation ability. Prodrug approach is the chemical modification of
active molecule to modulate its lipophilic behavior, increase perme-
ability and water solubility [69]. Targeted prodrugs contain chemical
entity along with parent drugs designed to approach enzymes or
transport system at the targeted site to be converted to active moiety.
Targeted prodrug approach based on redox chemical delivery to save
the chemotherapeutic potential of mustard alkylating agents was ap-
plied. Redox derivative of alkylating agent crossed the BBB and re-
tained in the brain for longer time. Pharmacokinetic studies demon-
strated enhanced lipophilicity and improved efficacy of alkylating
agents [70]. Enkephalins are alternative options to avoid serious side
effects related with morphine and other opoids but have limited per-
meability to BBB and underwent peptidase degradation. Tyr-D-Ala-Gly-
Phe-D-Leu (DADLE) is prodrug of enkephalins but unable to cross BBB
due to hydrophilic nature. To solve this problem, 1, 4-dihydro-
trigonellyl chemical entity was attached to the parent drug via spacer.
This targeted prodrug system retained the prodrug in the brain for
longer period of time. Peptidase enzymes in the brain removed the
spacer and released the active drug [71]. Prodrug approach has been
successfully utilized for delivery of neurotherapeutics to treat
A.R. Khan et al.
neurological disorders. Dopamine, pharmacologically effective for the
treatment of Parkinson's disease, is unable to cross BBB disease. L-dopa
is transported through L-amino acid transporter crossed BBB and con-
verted to dopamine in the brain [72].
2.2.3. Cell based therapy
Cell based therapy has gained attraction for effective delivery of
variety of drugs to treat neurological disorders and brain tumors. This
therapy involves macrophages and many types of stem cells as carriers
for delivery to brain [73]. Macrophages are migrated to brain through
paracellular and transcellular transport mechanisms [74,75]. They have
natural ability of phagocytosis, enables them to enter brain as Trojan
horses. During brain tumor and inflammatory conditions macrophages
are attracted and infiltrated toward brain. Macrophages are suitable
candidates for targeted delivery of NPs and diagnostic and imaging
agents to the brain tumor and neurodegenerative diseases. In in vitro
studies, gold nanoshells carrying macrophages for photothermal
therapy were infiltrated glioma spheroids [76]. Exosomes are nanove-
sicles, cargo large number of drugs and biological molecules [77].
Protein and lipidic nature of exosomes facilitate them to be fused with
the recipient cells and deliver the therapeutic agents. Ligands such as
peptides are attached to target the exosomes and macrophages at spe-
cific site in the brain. Rabies virus glycopeptides, tet-1 peptide and
EGFRvIII-specific antibodies for glioblastomas are ligands for exosomes
brain targeting delivery [78–80]. Stem cells could be used as vector for
delivery of cytokines, oncolytic viruses, and suicide genes to brain
[81–83]. Stem cells could be effective cargo for oncolytic virus to treat
the glioma. In a study, Mesenchymal Stem Cells carrying oncolytic
herpes simplex virus exhibited efficacious results in glioma-bearing
mice [84].
2.2.4. Nanocarriers as drug delivery system
Nanocarriers have gained importance and interest as permeation
enhancement nanovehicles of therapeutic molecules across BBB.
Nanocarriers have capability of targeted and site specific delivery of
anticancer, anti-Alzheimer's and anti-parkinson's drugs and protease
inhibitors, made them suitable candidates as carriers for neurological
disorders and brain tumor targeted delivery. Most of the research over
last several years was focused on polymeric NPs based on poly (lactic
acid) (PLA), poly (D.L-lactide-co-glycolide) (PLGA) and poly (glycolic
acid) (PGA) for brain targeted delivery [85]. Surface coating of poly-
meric NPs with PEG, chitosan, lectin and D-α-tocopherol polyethylene
glycol 1000 succinate (TPGS) conferred stealth and site specific tar-
geting abilities to the NPs. Chitosan NPs were synthesized and en-
capsulated with nucleotide (Bcl-2 siRNA-) and doxorubicin separately.
In vivo pharmacokinetic and biodistribution studies had shown similar
results irrespective of different nature of two drugs [86]. Conjugation of
NPs with cell penetrating peptides such as RGD, RVG and CDX po-
tentiated the brain uptake of nanocarriers. A study was performed to
evaluate the effect of CDX on BBB permeation ability of NPs. compared
to unmodified NPS, paclitaxel loaded NPs modified with CDX, sig-
nificantly, enhanced the median survival time and exhibited improved
antitumor efficacy. In addition to polymeric NPs, solid lipids NPs (SLNs)
are also efficient nanovehicles to increase the brain targeting efficiency
of drugs. Ligand conjugated SLNs are efficient carriers for site specific
therapy. SLNs could be effective cargo for neucleotide delivery to brain.
Conjugation of SLNs with cationic angiopep and encapsulation of
SiRNA efficiently delivered SiRNA to the glioma [87]. 5-fluoro-2,-
deoxyuridine (FUdR) have restricted ability to enter the brain. Wang
et al. synthesized 3′, 5-dioctanoyl-5-fluoro-2-deoxyuridine (DO-FUdR)
and incorporated in SLN. They observed that SLN improved brain up-
take up to two folds compared to FUdR [88].
Liposomal delivery of cereberal ischemic agents, opoid peptides and
antitumor agents has proved therapeutic importance of these nano-
carriers for brain targeting delivery. Cationic liposomes are positively
charged vesicles bind with negatively charged endothelium and
367
Journal of Controlled Release 268 (2017) 364–389
delivered through adsorptive-mediated endocytosis or phagocytosis
[89]. PEGylated liposomes functionalized with glutathione were en-
capsulated with doxorubicin and inhibited tumor growth in animal
bearing glioblastoma [90]. Monoclonal antibodies (mAbs) bind to
transferrin receptor OX26 and conjugation of PEGylated liposomes with
mAbs directed liposomal delivery to the targeted site [91]. Various
brain tumor targeting chemotherapeutic agents based on liposomal
delivery have been approved for therapeutic purposes. These are Dau-
noXome® (Lipoplatin), DepoCyt® (cytarabine), Ambisome®, Visudyne®
and Doxil/Caelyx® (doxorubicin) [92].
The therapeutic and diagnostic potentials of magnetic NPs in brain
tumor targeted delivery have been explored in the recent years.
Superparamagnetic iron oxide nanoparticles, or SPIONS could be di-
rected to the target site and distinguish tumor affected tissue from
healthy tissues. External magnetic field is applied to target them into
the brain tumor and also used in combination with radiotherapy for
brain tumor. Endothelial vascular cell adhesion molecule-1 (VCAM-1) is
detection indicator of brain metastasis and combination of SPIONS with
VCAM-1 helped in early detection of brain tumor [93]. SPIONS have
been used for tracking the therapy and act as MRI contrast agent.
Magnetoliposomes are liposome encapsulating magnetic NPs and are
conjugated with transferrin protein to facilitate brain uptake through
trasferrin receptor mediated delivery. Magnetoliposomes of paclitaxel
modified with anti-GPNMB antibodies increased 4 fold brain uptake of
paclitaxel. Liposomal delivery provided sustained release concentration
of paclitaxel in animals compared to unmodified delivery [94].
2.2.5. Intranasal drug delivery
Drug administered through nasal route of administration is ab-
sorbed into the systemic circulation. Drug absorption through nasal
respiratory epithelium follows transcellular and paracellular absorp-
tion, carrier-mediated transport, and absorption through trancytosis
mechanism [95]. Nasal drug delivery to the brain posed a big challenge
of BBB-mediated restriction. Administration of drug deep into the nasal
cavity approached nasal mucosa, led to direct transmission of drug into
brain via olfactory pathway. Olfactory pathway consists of olfactory
neurons that carry drugs from olfactory mucosa to the brain and is slow
process of drug transmission. Olfactory epithelium pathway is faster
way of drug transportation [96]. Drug is passed through olfactory
epithelium via paracellular mechanism into perineural space and
transferred directly to the brain [97]. Detailed description about in-
tranasal brain targeting is the main focus of this review.
2.3. Recent advancements in brain targeted drug delivery
2.3.1. Antibodies mediated drug delivery
Antibodies based therapy became famous over last decade.
However, restriction posed by the BBB and low brain permeability of
the antibodies limited the potential of antibody mediated therapy for
neurological diseases. mAbs are much large in size and unlike small
molecules, unable to cross BBB and approach target sites in the brain
Table 2 [98,99]. Although, no mAb has been approved for brain tar-
geted therapy but several mAbs are under clinical trials especially for
the treatment of Alzheimer's disease [100]. Alzheimer's disease is ac-
companied by the abnormal folding and deposition of amyloid beta
(Aβ) peptide and tau protein in the brain. Anti-Aβ mAbs, bapineuzumab
and solanezumab failed to achieve optimal level in brain and caused
imaging related abnormalities in clinical trials [101]. Recently, clinical
trials conducted on aggregated mAbs peptide, significantly decreased
amyloid plaque in the brain. Trials on large number of population are
desired to further evaluate clinical benefits. mAbs such as solanezumab
recognize and bind with soluble form of Aβ whereas, aducanumab and
gantenerumab target the insoluble and aggregated Aβ plaques in the
brain and ultimately remove it from brain [102]. Another class of novel
Abs is single domain antibodies (VHHs), depleted of light chain and
have only fully functional heavy chain to recognize the target site in
A.R. Khan et al. Journal of Controlled Release 268 (2017) 364–389

Table 1
List of FDA approved marketed products for brain targeting delivery.

Product name Active ingredients Year of approval Indication

Radicava Edaravone 2017 Amyotrophic Lateral Sclerosis (ALS)

Ingrezza Valbenazine 2017 Tardive dyskinesia
Austedo Deutetrabenazine 2017 Huntington's disease
Ocrevus Ocrelizumab 2017 Multiple Sclerosis
Xadago Safinamide 2017 Parkinson's disease
Spinraza Nusinersen 2016 Spinal Muscular Atrophy (SMA)
Zinbryta Daclizumab 2016 Multiple Sclerosis
Nuplazid Pimavanserin 2016 Hallucinations and delusions associated with psychosis
Aristada Aripiprazole lauroxil 2015 Schizophrenia
Vraylar Cariprazine 2015 Schizophrenia and bipolar disorder
Rexulti Brexpiprazole 2015 Schizophrenia
Plegridy Peginterferon beta-1a 2014 Relapse of multiple sclerosis
Aptiom Eslicarbazepine acetate 2013 Epilepsy associated seizures.
Vizamyl Flutemetamol F 18 injection 2013 Radioactive diagnostic drug for Alzheimer's disease
Brintellix Vortioxetine 2013 Major depressive disorder
Tecfidera Dimethyl fumarate 2013 Relapse of multiple sclerosis
Dotarem Gadoterate meglumine 2013 MRI based brain imaging

brain. Camelid is VHH recognizes the amyloid peptide and tau neuro-
fibrillary tangles (NFTs) involved in Alzheimer's disease. These Abs are
transported across BBB non-invasively and useful transmigrating agents
for BBB mediated therapy. Anti-Aβ and anti-tau VHHs were formulated
and administered I.V. in mouse to probe the plaque and NFTs in brain.
In vivo imaging technique had shown that VVH transmigrated across
BBB more efficiently than conventional IGg, bound to Aβ plaques and
recognized tau tangles. These finding suggested that VHSS could be
therapeutically and diagnostically important for targeting neurological
diseases [103].
Multiple sclerosis (MS) is another CNS disease characterized by
impaired connection between the brain and rest of the body. Myelin is
the protective sheath to insulate the axons and damaging of this sheath
leads to MS. Strategic treatment of MS based on mAbs involves deple-
tion of B cells, facilitation of remyelination and inhibition of immune-
cell trafficking [102]. Natalizumab depletes the B cells and T cells in the
CNS. It prevents the entry of T cells via alpha 4-integrin blockade in the
BBB [104]. Novel therapy of MS involves reduction of lymphocytes
count and is emerging approach for MS targeting. Ofatumumab is the
latest mAb that binds CD20 on B lymphocytes and depleted B cells via
complement-dependent cytotoxicity and antibody-dependent cell-
mediated cytotoxicity in phase II study Table 1 [105]. Ocrelizumab is in
final stage development, reduced the relapse rate for extended period of
time in phase II and phase III studies and significantly, decreased
number of lesions in the brain in phase III study [106,107]. Facilitation
of myelin repair is another latest approach for MS therapy. BIIB033,
anti-LINGO-1 mAb, is the first mAb that antagonizes LINGO-1, have
shown efficacy in myelin repairing model and safety in phase I safety
study [108,109].
Bispecific antibody (bsAb) is newly designed Ab with two different
binding specificities. bsAbs are introduced for chemotherapy with one
binding specificity targets the tumor cell and other targets the antigen
on immune cells [110]. Recent application of bsAbs is the targeted
delivery across BBB. bsAbs constructed with one specificity to promote
transportation across BBB via receptor mediated transport and second
specificity to target the specific site in the brain for desired therapeutic
effect. Several BBB crossing bsAbs were formulated and evaluated for
brain targeted delivery such as bsAb with transferrin receptor (TfR)
binding domain to cross BBB and single-chain variable region fragments
(scFv) specificity against amyloid beta peptide. mAb-scFv injected
subcutaneously in amyloid precursor protein transgenic mice, 60% re-
duced amyloid plaque. TfR and BACE1 targeting bsAbs were designed
through “knobs-into-holes technique. TfR binding domain of bsAbs had
shown low binding affinity with TfR, minimally altered normal function
of receptors and enhanced BBB penetration of BACE1 [111]. Whereas,
high affinity binding Abs were trapped in vascular compartment re-
sulted in poor penetration of BACE1to the target site.
Lipocalin-2 (LCN2) is a lipocalin protein secreted by the astrocytes
and microglia during brain hemorrhage, ischemic stroke and brain in-
jury. Astrocytes and microglia secreted LCN2 facilitates the inflamma-
tion during brain injuries. Various studies on multiple carcinoma re-
ported higher level of LCN2 expression in different tumors. Animal and
cell culture studies strongly recommended the involvement of LCN2 in
the progress of stroke, cerebral ischemia and brain injury. LCN2 gene is

Table 2
Summary of antibodies mediated brain targeting drug delivery.

Antibiody Recognition site/biomarker Neurological condition Outcomes Reference

Bapineuzumab and Soluble form of Aβ plaque Alzheimer's disease Reduction of amyloid plaque [101]
Solanezumab
Aducanumab and insoluble and aggregated Aβ plaque Alzheimer's disease Reduction of amyloid plaque [102]
Gantenerumab
Camelid – VHHs amyloid peptide and tau Alzheimer's disease Transmigration across BBB, recognition of Aβ [111]
neurofibrillary tangles and NFT
Bispecific antibodies transferrin receptor and Aβ peptide Alzheimer's disease Enhanced BBB penetration of BACE1 and [110]
reduced amyloid plaque
Natalizumab Alpha 4-integrin Multiple Sclerosis Depletion of B and T cells [103]
Ofatumumab CD 20 on lymphocytes Multiple Sclerosis B cell depletion [104]
BIIB033, anti-LINGO-1 mAb, LINGO-1 Multiple Sclerosis Myelin repairing [107,108]
LCN2 targetting Abs LCN2 Cerebral Ischemia, stroke and brain Reduced Inflammatory response [112]
injury
HMGB1 targeting mAbs HMBG1 Neuroinflammatory diseases Reduced inflammation and Enhanced [113]
neuroprotection

368
A.R. Khan et al.
modulated at transcription and translation level. Research on LCN2
explored that LCN2 is the target for drug therapy of neuroinflammatry
conditions. In near future, it is expected that scientists should focus on
the development of LCN2 inhibitors and LCN2 targeted neutralizing Abs
for brain ischemia, stroke and cerebral hemorrhage therapy [112].
High Mobility Group Box 1 protein (HMGBI) is actively or passively
secreted in trauma, chronic inflammatory disorders, autoimmune dis-
eases and cancer. HMGB1 initiates and maintains cytokine induced
inflammation and plays a role in variety of diseases. Strategies focused
on HMGB1 targeted delivery are most promising for neuroin-
flammatory conditions. Several mAbs and polyclonal Abs inhibit
HMGB1 and useful in the therapy of brain inflammatory medical dis-
eases such as stroke and hemorrhagic shock. In a study, rats were im-
munized with HMGB1/HMGB2 and anti HMGB1 mAbs were achieved.
In rat ischemic model, HMGB1 mAbs decreased BBB permeability and
remediated brain infarction. Anti HMGB1mAbs relieved the neuro-
pathic pain in sciatic nerve ligated rats. Sasaki et al. described that
mAbs provided neuroprotection in mouse Parkinson's model. HMGB1
like bsAbs have two domains, A and B Box. Box B mediates in-
flammation and Box A is competitor of HMGB1. Box A is the beneficial
and has antitumor effects. It provides protection in cereberal ischemia,
epilepsy and acute pancreatitis. It is suggetsed that Box A might be bind
with HMGB1 and compete with HMGB1 binding ligands [113].
2.3.2. Mfsd2a-based drug delivery strategy
Mfsd2a-based drug delivery strategy is the novel approach to target
the brain. Mfsd2a presents on the endothelial cells surface in the BBB,
prevents the transmission of molecules through trancytosis [114] and
facilitates the transport of specific lysophosphatidyl-choline (LPC) de-
rivatives [115]. Mfsd2a worked on two principles. One approach is
inhibition of Mfsd2a promotes the trancytosis in endothelium, re-
sultantly enhances BBB permeation. Tunicamycin and anti-Mfsd2a an-
tibodies are most probably reversible inhibitors of Mfsd2a [116].
Mfsd2a is transporter of LPC and derivatives of LPC such as LPC-DHA.
Mutation of mfsd2a blocks the transport of LPC to brain [117]. LPC act
as carrier for small molecules and transported through mfsd2a across
BBB. Second approach involves LPC mediated delivery resembling the
glucose transporter (GluT1) and L-type amino acid transporter (LAT1)
based transport [118,119]. Acquired immunodeficiency syndrome
(AIDS) induced encephalopathy was treated using this strategy. Efa-
virenz loaded nanocarriers functionalized with phenylalanine were
transported through LAT-1, similar to LPC, inhibited reverse tran-
scription of HIV into CNS [120]. LPC based delivery has several lim-
itations and is not applicable for all small molecular weight drugs.
Drugs transported through LPC must have one carboxylic group for
coupling with LPC.
2.3.3. Facial intradermal injection
In addition to intranasal brain targeting, facial intradermal injection
overcomes the BBB through trigeminal neural connection. Trigeminal
pathway consists of vasculature, perineurium and epineurium interlinks
facial skin with brain. This pathway is involved in facial intradermal
targeting of brain. Yu XC et al. compared intranasal delivery with in-
tradermal injection for brain targeting in the rats. Compared to in-
tranasal injection, intradermal injection into the rat mystacial pad,
significantly, enhanced brain targeting efficiency, direct transport per-
centage and brain concentration of Evans blue (EB). Transport of EB
from mystacial pad and nasal mucosa to brain was mediated through
lymphatic system. Facial dermal delivery explored epineurium, peri-
neurium, neurons and Schwann cells for brain targeting [121].
2.3.4. Laser light based technology
Laser light based technology could be beneficial in BBB disruption
and helpful in glioma targeted delivery. Laser light causes defects in
membrane of endothelial cells and endothelial cells become leaky,
allow transport of therapeutic agents to parenchymal tissues [122]. 5-
369
Journal of Controlled Release 268 (2017) 364–389
aminolevulinic acid (5-ALA), prodrug approved for photodynamic
therapy, is exciting molecule for glioma treatment. Combination
therapy of laser with 5-ALA opened the tight junctions between the
endothelial cells for longer period of time. Laser could be combined
with other strategies to potentiate BBB disruption. Nanoparticles com-
bination with laser is appealing approach for glioma targeting. Ultra-
short laser pulses were applied and successfully transported nano-
particles, genetically engineered viruses and numerous therapeutic
agents to the brain [123].
2.4. Comparison of current approaches for CNS drug delivery
BBB is a major challenge in brain targeting. Invasive and non-
invasive approaches to disrupt the protective BBB were explored for
effective therapy of neurological disorders. Invasive approaches involve
hyperosmotic and vasoactive agents that transiently disrupt the BBB.
This disruption results in opening of tight junction between the en-
dothelial cells and promotes transport of drugs to brain. However,
chemical disruption has drawbacks of neurotoxicity and disturbance in
brain functions. Alternative invasive approach is FUS delivery involve
MBs to increase BBB permeability. FUS combined with NPs and lipo-
somal delivery for direct targeting the brain tumor. HIFU enhances the
transport of chemotherapeutic agents to the brain tumor. Intracerebral
and intraventricular injection directly deliver drug to brain parenchyma
through catheter. This technology requires very precise mapping of the
injection or implantation site to achieve maximum targeting of the drug
to the tumor. Convention enhanced delivery utilized catheter linked
reservoir to provide slow delivery and reduce toxicity of chemother-
apeutic agents. One study reported toxicity of paclitaxel while using
CED and this delivery strategy is not more beneficial than other stra-
tegies in improving survival rate. Wafers and microchips are polymeric
devices implanted to provide controlled delivery of drugs to brain.
Wafers are useful therapy in recurrent and newly diagnosed glio-
blastoma. Wafers technology is unable to deliver drug into deep brain
tissues and brain injuries involving impaired wound healing and ab-
scess formation limited their potential. Despite of therapeutic im-
portance of invasive approaches in brain disorders, invasive techniques
are limited to well define brain tumors. These techniques involve sur-
gical procedures and have risk of brain infections. Mechanical instru-
ments might cause brain injuries including thrombosis.
Keeping in view of risks associated with invasive strategies, non
invasive approaches were designed to treat life threatening brain dis-
orders. P-gp efflux prohibits lipophillic and low molecular weight drugs
to enter the brain. Cyclosporine A, valspodar, elacridar and zosuquidar
inhibit P-gp efflux and facilitate brain delivery. Toxicity has been re-
ported with efflux inhibitors especially with first generation inhibitors.
Prodrug was introduced to modulate lipophilic characteristic of drugs.
Prodrug approach is based on reducing the number of polar groups of
hydrophobic drug or linking it with lipophilic moiety. This conversion
requires challenging engineering skills and not fruitful. Stem cells could
be cargo for brain delivery. Multiple stem cell types have been shown to
exhibit inherent tropism toward brain tumors. Stem cells have been
used to cargo suicidal genes, cytokines and oncolytic viruses. Stem cells
based brain delivery failed to produce positive results in clinical trials.
Non availability of standardized protocol led to difficulty in inter-
pretation of in vivo results from in vitro data and lack of skills in en-
gineering of oncolytic virus loaded stem cells restricted stem cell based
delivery. Colloidal carriers promote the transportation of therapeutic
moieties for neurological disorders. Combination of nanoparticles with
other strategies provided fruitful results. Biligands targeted nano-
carriers for dual targeting of BBB and brain parenchyma have gained
attention of scientists now a days. Diffusion of nanocarriers to the
parenchyma is uncertain and depends on their surface characteristics.
All invasive and non invasive approaches have limitations in brain
targeting. Most of the approaches disrupt the BBB or promote BBB
delivery and not bypass the BBB. IN delivery is non invasive, bypass the
A.R. Khan et al. Journal of Controlled Release 268 (2017) 364–389

BBB without absorption to blood and direct target the brain. Intranasal
delivery is useful approach and reliable alternative CNS delivery.
Various colloidal carriers successfully explored IN neural pathway for
brain delivery. This route avoids exposure of drugs to the peripheral
organs and non toxic to them. IN route requires small amount of drug to
produce therapeutic response. Recently, patients operated nasal drug
delivery devices to deliver drugs deep into the nasal cavity have been
introduced. Direct brain targeting IN approach is safe and not alter
normal physiological functions of brain and avoids injuries to brain.

3. Nasal drug delivery to brain

Fig. 2. Pathways of IN delivery of drugs.
Nasal route has been explored for decades for systemic delivery of Reprinted from [135].
drugs which can't be given via oral route but now it has gained at-
traction and potential for direct IN delivery of neurotherapeutics to
3.2. Mechanism of nasal drug delivery to brain
brain by circumventing the blood circulation, thus reducing the sys-
temic exposure and hepatic/renal clearance [124,125]. This pathway
When the drug is administered to nasal cavity, it has to cross the
involving olfactory and trigeminal nerves is gained an important con-
mucous layer and constantly beat cilia. Ciliated columnar cells in the
sideration for delivery of wide range of therapeutic agents even plas-
nasal epithelium control the movement of cilia. These cilia are im-
mids can be delivered to brain safely and effectively [126,127].
mobile in olfactory region, not having dynein arms required for moti-
lity, whereas they motile in respiratory region. After crossing this bar-
3.1. Pathways of nasal drug delivery
rier, drug is transported across nasal mucosa either transcellularly or
paracellularly as depicted in Fig. 3.
3.1.1. Olfactory pathway
The possible mechanism by which drugs are transported from nose
to brain has not yet clear but olfactory pathway contributes a vital role. 3.2.1. Transcellular transport
This pathway consists of olfactory epithelium, lamina propria and ol- Receptor mediated endocytosis is the transport pathway of molecule
factory bulb. Olfactory epithelium contains three types of cells; neu- through different BBB endogenous receptors. Clathrin-dependent or
ronal cell, progenitor cells and supporting cells, and all are connected independent mechanisms of receptor mediated endocytosis are in-
by tight junctions. Neuronal cells start from olfactory bulb in CNS to volved for transcellular transport [136]. Nicotinic acetylcholine re-
olfactory epithelium in nasal cavity and provide information to brain ceptors are present in the olfactory epithelium, bulb and trigeminal
[128]. Basal cells and neural cells replace each other during their ganglions and these receptors are involved in the receptor mediated
constant motion and due to this constant motion and replacement nasal endocytosis. Particle size is important in deciding the mechanism of
mucosa becomes permeable resulting in enhanced delivery of drug to endocytosis, for example, particles having size less than 200 nm are
brain [129]. Nasal epithelium protects the brain from entry of harmful followed through clathrin-dependent endocytosis whereas, particles in
substances which are entrapped by the mucus layer on epithelium and the range of 100–200 nm are transported through caveolae-mediated
cleared by cilia. Lamina propria lying on nasal epithelium has blood endocytosis [137]. Other factors which contribute to endocytosis
vessels, mucus secreting glands, olfactory axons and maxillary branch pathway are cell type, surface charge and concentration of the particles
of trigeminal nerve [130,131]. Olfactory axons are separated into group applied to the cells [138]. Transport of molecules through transcellular
of 20's and are surrounded by the sheath of Schwann cells restricting mechanism is slow and time taking process.
perineural transport by decreasing space between axons. This feature of
ensheathing the axons is called filia olfactoria [132]. Olfactory bulb is
3.2.2. Paracellular transport
projected to different regions of brain such as piriform cortex, amygdale
In nasal epithelium, cells are connected with each other through
and hypothalamus, thus helpful for direct nasal delivery of drugs to
different junctions such as tight junction, zonula adherens and macular
brain.
adherens [139]. These junctions are impermeable to large molecule
drugs but due to continuous turnover of neuronal and basal cells be-
3.1.2. Trigeminal pathway
come permeable [140]. Opening of these junctions promotes the
Trigeminal pathway also plays an important role in IN delivery of
paracellular transport. It has been reported by different studies that
drug. Respiratory region occupies major portion of nasal cavity and
innervated by trigeminal nerves. Trigeminal nerve is fifth (V) cranial
nerve having three branches; ophthalmic nerve, maxillary nerve and
mandibular nerve and is responsible for sensation in nasal cavity.
Ophthalmic and maxillary nerves innervate the nasal mucosa and carry
the necessary information from nasal cavity to CNS. Various DDSs
target these two branches for transport of drug to different parts of
brain [133]. Trigeminal nerve innervating nasal cavity enters to
brainstem through pons, whereas it enters to forebrain through cribri-
form plate, thus promoting the entrance of drug to caudal and rostral
parts of brain and are main focus for IN transport of drugs to brain.
Olfactory pathway delivers drug to rostal area of brain, whereas tri-
geminal pathway not only targets rostal but also caudal area of brain,
making it difficult to differentiate whether intranasally administered
drug is translocated to rostal area by olfactory or trigeminal pathway
[134]. As a result, when drug is intranasally administered to brain, it
may be transported via olfactory or trigeminal pathway as depicted in Fig. 3. Possible mechanisms for IN delivery of drugs to brain.
Reproduced from [5].
Fig. 2.

370
A.R. Khan et al.
various DDSs by opening these junctions are rapidly transported
through nasal mucosa to brain as depicted in Fig. 3.
3.3. Factors affecting nasal drug delivery to brain
3.3.1. Physiochemical properties of drugs
Physiochemical properties of the drugs alter drug transportation
across nasal mucosa. Transmigration of low molecular weight drugs is
not affected by the physiochemical characteristics of drugs.
Transportation of drugs with molecular weight of more than 300 Da is
dependent on their physiochemical properties [141]. Molecular size of
product decides about the rate of permeation through mucosa. Mac-
romolecular drugs such as protein, peptides and genes achieved low
level of drug in brain due to high molecular weight and hydrophobic
nature [142]. Particle size and surface properties of drug particles play
a vital role in nasal drug delivery. Very fine particles are deposited in
the lungs and are not considered in nasal products. Particle size in the
range of 5–10 μ is an ideal for designing nasal formulations. Particle
size and morphological characteristics of particles must be considered
with respect to nasal mucosa irritation and feel of grittiness [143].
Polymorphic forms of a drug have different nasal membrane permea-
tion abilities. Polymorphism affects the delivery of drug across nasal
epithelial membrane. Stability and purity of polymorphic forms should
be focused for nasal formulations preparation.
pH of nasal mucosa and formulation and pKa of the drugs are im-
portant to be considered while formulating a DDS. Nasal irritation,
mucosal damage and bacterial growth are prevented when pH of for-
mulation is adjusted to 4.5 to 6.5 [143]. Size of the nasal cavity is
limited and it accommodates 25 mg/dose and 25 to 200 μL per nostril.
Nasal mucosa facilitates the permeation of non-ionized portion of a
drug. Permeation of electrolytes and polar drugs depends on their de-
gree of ionization and pKa, respectively. Nasal mucosa promotes the
transmigration of lipophilic and low molecular weight drugs. High
molecular weight and hydrophilic drugs are easily removed by the
mucociliary clearance and unable to cross nasal mucosa. Nasal mucosa
also has hydrophilic components and highly lipophilic drugs do not
cross nasal epithelium and are cleared from nasal cavity. Various
techniques used to enhance hydrophilic characters of drugs. Prodrug
approach is used to design inactive hydrophilic moiety of active lipo-
philic drug. Prodrugs of L-Dopa were designed and reported to sig-
nificantly, enhanced penetration through nasal membrane than active
drug. Prodrugs of highly lipophilic drugs promote transmemberane
nasal delivery of drug. Peptides and protein based drugs underwent
enzymatic degradation in nasal cavity. Prodrug has successfully pro-
tected them from peptidal degradation and facilitated nasal drug de-
livery. L-aspartate-β-ester prodrug of acyclovir was designed and re-
sulted in enhanced permeability across nasal epithelium and protection
from enzymatic degradation than parent drug. Chemical form of a drug
decides its fate of mucosal permeation. Salt or ester form of a drug is
easily permeated through membrane.
3.3.2. Formulation factors
Targeting of drugs deep into nasal mucosa is the utmost require-
ment of targeted nasal drug delivery to brain. Nasal drops and tradi-
tional sprays are unable to deposit drug in olfactory epithelium. These
traditional devices are useless for targeting brain through olfactory
pathway. Computational fluid dynamics (CFD) study using spray device
was conducted to investigate drug deposition at olfactory region. This
study revealed that spray devices were failed to deposit drug in olfac-
tory region [144]. Standard spray bottles are not ideal candidates for
olfactory deposition. Oxytocin was delivered through nasal spray and
produced variable response in different treatment groups [145]. Com-
pared to tradational spray pumps, droplets produced from nebulizer,
upon nasal inhalation deposited to the upper posterior region of the
nasal cavity, thus promoted nose to brain targetting. IN drug delivery to
brain dependent upon the dosage forms, formulation systems and
371
Journal of Controlled Release 268 (2017) 364–389
delivery device. Physical form of a formulation affect IN delivery. Li-
quid formulations are washed out with mucociliary clearance more
easily than powder form. Powder formulations stick to moist surface of
nasal mucosa and retained for prolong time.
Tonicity of formulation is contributing factor in mucosal permea-
tion. Hypertonic solution shrinks the nasal epithelial cells and facil-
itates nasal mucosal permeation. Hypertonic solution and low pH pre-
vent the movement of cilia and enhance the transmucosal delivery by
reducing mucociliary clearance. IN delivery demands prolong contact
of drug with nasal mucosa. Visosity enhancing, mucoadhesive and
gelling agents increase contact time with mucosa. These agents de-
crease mucociliary clearance and increase permeation through mucosa.
DDSs such as polymeric NPs, mucoadhesive microspheres and nanogels
work through these mechanisms and provide sustained release of drug
over prolong period of time. Excipients used in nasal formulations
should be non toxic and selected according to their functions.
Excipients have been reported to cause nasal irritation. In liquid nasal
formulaitions glycol, alcohol and glycerides are used as solublizer to
enhance the solubility. Surfactants and cyclodextrins, solublizers and
stabilzers are alternative to alcohols. Liquid formulations contain
parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA and
benzoyl alcohol as perservatives. Preservatives based on mercury irre-
versibly inhibit ciliary actions and are prohibited for nasal delivery.
Allergic rhinitis and chronic nasal conditions lead to dryness of nasal
mucosa. Nanogels for IN delivery contain humectants to keep mucosa
humid and prevent mucosal damage. These are glycerin, sorbitol and
mannitol.
3.3.3. Physiological and anatomical considerations
Movement of cilia and mucus are natural defense mechanism to
protect respiratory system from invading foreign bodies including
bacteria. Mucus entrapping foreign particle is cleared with action of
continuous beating cilia. Mucociliary clearance removes the drug and
formulation systems from nasal cavity and decreases the contact time
with the mucosa, ultimately leading to decrease drug delivery to brain
[146]. Nasal clearance half life of the formulations is about 12–15 min
[147]. Pathological conditions, hormones and viscosity enhancing
agents reduce the mucociliary clearance and promote transmucosal
delivery. Physiological conditions of mucosa alter drug transportation.
There are various conditions of mucosa such as dry, bleeding, rhinor-
rhea, sinitis, or nasal infection. In allergic or excess mucus secretion
conditions, drugs are washed away from nasal mucosa before permea-
tion to neural pathways [148]. Pathological diseases such as cystic fi-
brosis, Kartagener's syndrome or Sjogrens syndrome decrease mucosal
clearance.
Various enzymes exist in nasal cavity and alter nasal drug delivery
to brain. Cytochrome P-450 is oxidizing enzymes present in nasal
cavity. Other forms of CYP 450 are hydrolases, oxidoreductase, lactate
dehydrogenase, acid phosphatase and esterase. Oxidative Phase 1 and
conjugative phase II enzymes have also been reported in nasal cavity.
Peptidase and proteases present in the nasal cavity restrict nasal de-
livery of peptide and protein based drugs to brain [149]. Metabolic
activity of these enzymes is less than hepatic enzymes but their im-
portance in altering pharmacokinetic and pharmacodynamic profile of
drugs can't be ignored. Enzyme inhibition and prodrug design are ef-
fective approaches to save the therapeutic efficacy of nasal products
from metabolic degradation.
Inner of the nasal cavity is covered with respiratory epithelium
which lies interior to nasal valve and not target for IN delivery. Nasal
valve is a narrow opening in the nasal cavity, created a barrier for
delivery of drug to brain. It is located 2-3 cm from nostril with cross
sectional area of 0.5 to 0.6 cm2 [150]. Posterior part of the nasal cavity
houses neural connection to brain. Targeting the drug to the posterior
and upper part of the nasal cavity beyond the nasal valve is demanded
for effective IN neural delivery. Nanoformulations failed to target this
part of the nasal cavity, whereas latest nasal drug delivery devices have
A.R. Khan et al.
Table 3
Potential therapeutic agents for nasal drug delivery to brain.
Therapeutic agent Disease Outcomes
Insulin Alzheimer's disease, Cognitive Improve verbal memory and reduce general cognitive decline
impairment
Oxytocin Autism spectrum disorders Pro-social effects.
Orexin-A Narcolepsy Improve CNS hypocretin signaling and also olfactory dysfunction
Leptin Obesity Reduce appetite and induce weight loss
Benzodiazepine i.e. Midazolam Seizures Replacement of rectal and IV administration as cheaper, easy to use and more
efficacious.
Naloxone Opioid overdose Reverse the effects of opioid overdose more effectively
Perillyl alcohol Brain metastasis Increase efficacy and less side effects
got potential to deliver drug deep into the nasal cavity housing neural
connection to brain. Erectile tissues of medial and lateral walls of the
nasal cavity control the physiological nasal cycle. Normal nasal cycle is
associated with alternating congestion and decongestion of nostrils
[150]. Nasal cycle lasts for 1–4 h and accompanies with congestion of
one nostril and flow of air through other nostril. During alternating
cycle nasal delivery of drug through congested nostril beyond nasal
valve is prohibited. Various factors alter normal nasal cycle such as
physical activity, sexual and emotional behaviors and inflammatory
conditions. Shape of the plumes produced by nebulizers, spray pumps
and metered dose inhalers does not match with the triangular shaped
nasal vestibule and labyrinthine geometry beyond the nasal valve.
Particles present in the periphery of the plume penetrate to lower part
of nasal cavity and pass to lower part but requirement of efficient nasal
delivery to brain is targeting the drug to upper part of the nasal valve.
Venous vasculature and lymphatic system drain the nasal cavity.
Venous drainage comprises of external jugular veins and cavernous
venous sinuses. External jugular veins drain the anterior region of the
nasal cavity, whereas cavernous venous sinuses drain the region beyond
the nasal valve, the part of nasal cavity housing olfactory olfaction.
Nasal cavity has not true lymphatic drainage, the perivascular spaces
along the olfactory and trigeminal nerves and alongside cerebral ar-
teries and veins, may act as lymphatic drainage between the nasal
cavity and brain. Lymphatic system plays its role in the transport of
drug molecules between nose and brain.
3.4. Therapeutic applications of nasal drug delivery to brain
IN delivery is emerging as an efficient and effective method of de-
livering a variety of drug molecules such as growth factors, hormones,
neuropeptides, stem cells and chemotherapeutic agents to brain (sum-
marized in Table 3). It represents a promising therapeutic strategy for
the treatment of diseases with CNS involvement, such as obesity, Alz-
heimer's disease, Parkinson's disease, Huntington's disease, depression,
anxiety, autism spectrum disorders, seizures and stroke [127].
3.4.1. Nasal delivery of proteins based drugs
Peptides and proteins based drugs administered via oral route un-
derwent enzymatic metabolism and are unable to enter the brain due to
large molecular size. Nasal administration of such compounds targets
them to the specific region of brain [151]. Usually peptide and protein
drugs are administered via parentral route because of physiochemical
instability and first pass elimination but IN delivery seems to be pro-
mising option. Different studies on human and animals resulted in
successful IN delivery of large number of protein based molecules to
brain, such as corticotropin-releasing hormone (CRH), neurotrophic
factors, insulin and MSH/ACTH [152]. Therapeutic role of Insulin-like
growth factor (GF-1) in stroke was evaluated by IN administration in
rats with middle cerebral artery occlusion (MCAO). IN administration
of IGF-1 not only helped in decreasing stroke volume but also improved
neurological function [153].
372
Journal of Controlled Release 268 (2017) 364–389
Reference
[163,164]
[165]
[166]
[167,168]
[169,170]
[171]
[172]
3.4.2. Nasal delivery of stem cells
Danielyan L et al. studied IN delivery of stem cells and suggested
that stem cells administered by the nasal route followed olfactory
pathway and reached olfactory bulb and other parts of brain including
brain parenchyma. They also investigated that stem cell transplantation
in Parkinson's disease was complicated surgical procedure and nasal
delivery of stem cell was reliable alternative to surgical procedure
[154]. Neural stem/progenitor cells (NSPC) have recently gain poten-
tial for treatment of intracerebral glioma by IN delivery. IN delivered
NSPC was reported to rapidly migrate to malignant glioma via olfactory
pathway [155]. Genetically modified NSPC are under phase-I clinical
trial in humans, they have ability to carry an enzyme which converts
prodrug 5-flurouracil to active drug flurouracil during surgery when
administered through intracerebral route [5]. NSPC have useful po-
tential to carry biological active genes products targeting tumor, as well
as reversal of other pathological and inflammatory process or defi-
ciency in the brain with reduced systemic exposure. IN delivery of NSPC
provides non-invasive and chronic therapy for treating gliomas and
other CNS disorders [155,156].
3.4.3. Nasal delivery of chemotherapeutic agents
Administration of anticancer drugs by parenteral or oral route to
target the brain tumors not only limited the efficacy of these agents by
BBB but also caused serious side effects on other organs; therefore, the
nasal route of drug delivery has been explored by researchers. Many
chemotherapeutic agents such as Perillyl alcohol (POH) [157], NSPCs
[155], glioma-adapted vesicular stomatitis virus strain (VSVrp30)
[158], methotrexate [159] and telomerase inhibitors (GRN163) [160]
have been successfully delivered to target brain tumors by nasal route.
It was reported from animal and human studies that IN delivery of
drugs for treatment of brain tumor has a bright future. To design a new
molecule for treating brain metastatic breast tumor, Dr. Thomas Chen
and NeOnc Technologies conjugated temozolomide (TMZ) with POH
for IN delivery and the computer modeling results demonstrated the
successful delivery to brain of this moiety [161]. By utilizing this
concept, Schonthal investigated the effect of this TMZ-POH conjugate
by IN inhalation in animals with breast cancer induced brain metas-
tasis. It was observed that IN delivered conjugate not only enhanced the
chemotherapeutic effects on breast cancer cell lines but also increased
the half life of TMZ without observable side effects and increased the
survival time of treated animals than control animals [162]. Brain
tumor causes damage to BBB and helpful for transport of drug across
BBB but systemic exposure by nasal delivery is very less suggesting this
route of delivery may provide different and more efficient route of
accessing tumor.
4. IN brain targeting novel DDSs
The DDS is designed to transport the drug at particular site in the
body, attain desired therapeutic drug level and maintain plasma drug
concentration within therapeutic window. The DDSs release the drug at
predetermined rate and maintain the drug plasma concentration for
A.R. Khan et al.
desired duration. Colloidal carriers such as NP, liposomes and micro-
spheres have got potential to achieve desired therapeutic level in target
tissues for required duration for optimal therapeutic efficacy by con-
trolling the drug release rate [173]. The scope of these colloidal carriers
for nose to brain targeted DDSs is focus of discussion in this review.
Drugs and carriers which are used as DDSs to explore direct nose to
brain pathways are summarized in Table 5 (Fig. 4).
4.1. Critical attributes of IN DDSs for brain targeting
Nanoparticulate systems provide controlled and BBB circumvented
delivery for effective therapy of neurological disorders. IN nanovehicles
reduce the dose related side effects in non targeted tissues and improve
patient's compliance Table 4. Desired properties of nasal drug delivery
formulations are summarized as under:
• Polymers used for colloidal delivery should be non toxic, biode-
gradable and biocompatible.
• In vitro and in vivo stability of the nanoconstructs is utmost im-
portant. Size of the nanocarriers is deriving factor for efficient de-
livery. Intranasally administered colloidal NPs with 20 nm diameter
are transported extracellularly to the brain. Olfactory pathway de-
mands NPs with diameter less than olfactory neurons for in-
tracellular transport to brain. Particle size is important in deciding
the mechanism of endocytosis, for example, particles having size
less than 200 nm are followed through clathrin-dependent
373
Journal of Controlled Release 268 (2017) 364–389
Fig. 4. Schematic presentation of nasal drug delivery to
brain.
endocytosis whereas, particles in the range of 100–200 nm are
transported through caveolae-mediated endocytosis
• In addition to size, charge on the NPs is also an important con-
sideration while designing formulation. Zeta potential is measure of
stability of the resultant nanocarriers. NPs must have ˃ ± 30
electrical potential to induce static repulsion on reproach and fa-
cilitate NPs – cells interaction.
• There should be minimum interactions between polymer, drug and
excipients such as emulsifiers and surfactants to avoid chemical
degradation, alteration or protein translation.
• It is likely to prolong stay of drug carriers at nasal mucosa by using
various mucoadhesive agents. Nanoformulations should be able to
reduce mucociliary clearance. Avoiding of NPS aggregation on in-
teraction with mucus is desirable for effective delivery. Liposomes
and other lipid based DDSs reduce mucociliary clearance. Viscosity
enhancing and gelling agents provide sustained release properties to
the carriers and prolong stay at nasal mucosa.
• Non toxic and appropriate concentrations of the excipients are re-
quired for designing colloidal carriers. Nanocarriers should not
cause irritation and damage to nasal mucosa.
• DDSs should have excellent drug loading and release the drug at
desired rate. However, high loading delays the release of drug from
DDSs. NPs storage stability is mandatory to be ensured.
• DDSs open the tight junctions between nasal epithelial cells and
promote the drug delivery through these junctions. Paracellular
transport is slow process. Various endocytic transport mechanisms
A.R. Khan et al. Journal of Controlled Release 268 (2017) 364–389

Table 4
Pros and cons of nanocarriers for nose to brain delivery.

Delivery systems Pros Cons

Polymeric NPs Reduce mucocilliary clearance, increase residence time on olfactory region
and enhance permeation through mucosa and conjugation with variety of
ligands for targeted delivery
Peptide modified NPs Targeted delivery of macromolecular drug such as insulin
Solid lipid NPS Non toxic to nasal mucosa, controlled release properties, increase the stability
of encapsulated drugs and deliver peptides and macromolecular drugs
Nanoemulsions Enhance the permeability across nasal epithelial cells, promote nasal delivery
of small molecular weight hydrophobic drugs, nucleotides and genes
Micelles Ligand based targeted delivery of nucleic acids and genes
Nanogels Enhance the deposition of drug at nasal epithelium and residence time in
nasal cavity, delay release of drugs, overcome the bioavailability related
problems, deliver radioactive nucleotides and combined with other DDSs.
Liposomes Encapsulation of small and large molecules with a wide range of
hydrophilicity and pKa values, prevent enzymatic degradation and mucosal
membrane disruption, sustained release of drug and mild toxicity.
Microcarriers Provide mucoadhesion and combined with other DDSs for delayed release of
drugs
Mucosal damage, nasal irritation, toxicity associated with lectin
conjugated NPs and mechanism of NPs neuronal uptake is unclear.
Toxicity associated with CPPs mediated delivery
Low entrapment efficiency and storage related problems
High concentration and a narrow range of physiologically acceptable
surfactants and co-surfactants and concentration in different parts of
brain varies with each agents
Surfactants related complications have been reported
Mechanism of enhanced drug transport to brain is unclear. It may be due
to prolonged stay at nasal mucosa or altered permeability of nasal
epithelium
Liposomal delivery is passively targeted rather than active targeting
Patient's position during and after delivery influences the clearance of
microparticles

Table 5
Drugs and DDSs for direct nose to brain targeting.

Therapeutic agent Drug delivery system Problems Therapeutic Benefits Ref.

Camptothecin Tat modified Micelle Less cytotoxicity, less efficacy Improved cytotoxicity and efficacy. [214]
Phytochemicals i.e. curcumin and Mesoporous silica NP Poor solubility, less brain uptake Improved brain uptake [238]
chrysin
Nucleotide Nucleotide NP Less brain uptake, low efficacy Increased brain uptake, improved efficacy [239]
Olanzapine Polymeric micelle Low brain permeability Enhanced Drug targeting to brain [240]
Risperidone Polymeric NP Poor oral bioavailability, non targeted delivery High brain uptake, high bioavailability [241]
Venlafaxin Polymeric NP Poor oral bioavailability, slow onset of action Quick onset of action, high brain uptake [242]
GDF-5 Lipid microemulsion Neuronal degeneration Increased in drug targeting [243]
Zonisamide Microemulsion Limited uptake across BBB, High first pass High brain uptake, high bioavailability [244]
metabolism
Midazolam PLGA NP Less brain uptake and less targeting of drug Enhanced drug entrapment, stability and controlled [245]
release.
Ropinirole In situ gel Limited uptake across brain, low oral High targeting efficiency, enhanced brain uptake [218]
bioavailability
Olanzapine Nanoemulsion High P-gP efflux, high first pass metabolism High therapeutic efficacy, high bioavailability [246]
Valporic acid Solid Lipid NP Less efficacy, less brain uptake Enhanced brain uptake, improved efficacy [247]
Rivastigmine CPP-Liposomes Less brain uptake. Improved brain delivery and enhanced [225]
pharmacodynamics
Estradiol Polymeric NP Low permeability, nasal mucocilliary clearance High brain uptake, enhanced retention [248]
Insulin Solution Cognitive deficits Improved memory [249]

are involved in IN drug delivery to brain. DDSs rapidly deliver drug
molecules via transcellular transport to brain.
• Combination of IN DDSs with vasoconstrictors supplements the drug
delivery to brain. Phenylephrine inhibited absorption of drug to
systemic circulation across respiratory epithelium and promoted
drug transportation through olfactory epithelium.
4.2. Nanocarriers as nose to brain DDSs
4.2.1. Nanoparticles (NPs)
Among various available formulations, NPs provide an excellent
platform for direct transport of drug to brain by protecting drug from
biological and chemical hazards and preventing the efflux of drug to
enhance drug brain concentration Fig. 6 [3]. NPs with particle size of
10–300 nm are designed to encapsulate and deliver wide variety of
therapeutic agents across olfactory pathway to brain [174]. Various
human and animal studies have shown that IN delivered NP may en-
hance brain uptake, improve pharmacological activity or therapeutic
efficacy and reduce side effect of drugs compared to conventional DDSs
as depicted in Table 5.
From literatures, it is obvious that the mechanism of transport of
NPs from nose to brain via olfactory pathway is still unclear. Scientists
have not explored whether drug is released in nasal cavity and trans-
ported to brain or NPs carrying drugs are directly delivered via neural
connection [3]. Most research was focused on increase in drug con-
centration in brain, and improvement in efficacy and not on evaluating
mechanism of drug transports [175–177]. Transport of NPs depends on
morphology and surface characteristics [178]. NPs having hydrophilic
characteristics are transported paracellularly and those with hydro-
phobic characteristics are transported transcellularly [179]. Various
types of novel NP with different potential applications are discussed in
this section.
4.2.1.1. Polymeric NPs. Various biodegradable and biocompatible
polymers have been studied for lN drug delivery of NP to the brain.
Among them, chitosan is reported to exhibit additional benefits of
bioadhesive properties, reduce mucocilliary clearance, increase
residence time on olfactory region and enhance permeation through
mucosa by opening of the tight junction between epithelial cells,
gaining potential for transmucosal drug delivery [180,181]. Chitosan
NPs can be used to deliver wide variety of drugs and nucleotides for
treatment of neurological disorders and brain tumors. For example,
Woensel MV et al. used chitosan NPs to deliver small interfering RNA
(siRNA) to CNS in mice for studying its effect on Gal-1 for treatment of

374
A.R. Khan et al.
glioblastoma multiforme and observed that after IN administration,
siRNA were detected in hindbrain by rapidly passing through olfactory
pathway. They concluded that chitosan NP is an excellent formulation
for delivery of biological active agents to target the brain tumor [5].
Similarly Mittal et al. incorporated rasagiline in chitosan glutamate NPs
(RAS-CG-NPs) for IN delivery to brain. They observed, significantly,
higher drug concentration of IN (RAS-CG-NPs) than that of free drug
solution and IV administered (RAS-CG-NPs) in brain. This study
indicated the potential of chitosan NPs in the treatment of Parkinson's
disease via direct intranasal brain targeting [182]. Another
neurological study supporting the role of chitosan NPs for treatment
of Parkinson's disease was conducted by Md et al. Stable chitosan NPs
were designed and encapsulated with bromocriptine. Intranasally
administered CS NP exhibited higher brain/blood ratio of drug
compared with IV administered CS NPs and IN drug solution. The
increase in drug concentration in CNS and enhanced clinical responses
were proof of direct nose to brain transport of chitosan NPs [183].
In addition to chitosan NPs, other polymeric NPs such as poly lactic-
co-glycolic acid (PLGA) have also been studied for exploring neural
connection between nose and brain. PLGA is also a biocompatible and
biodegradable polymer and is important in improving drug stability like
polyethylene glycol (PEG) and polylactic acid (PLA) [184,185]. The
uptake of PLGA NPs on olfactory ensheathing cells was studied and
compared with PLA and chitosan NPs by loading rhodamine using
confocal microscopy. Higher level of rhodamine incorporated PLGA
NPs was found in olfactory cells than that of PLA and chitosan NPs.
Treated cells had shown higher value of zeta potential than that of
control cells, whereas unloaded PLGA NPs had shown highest value,
confirming microscopy data. This study concluded that PLGA NPs could
be preferred over other polymeric NPs for brain targeted delivery via
olfactory neurons [186]. PLGA NPs could improve the brain uptake of
encapsulated drug when administered by nasal route. For example,
olanzapine, used for psychosis, underwent enzymatic metabolism and
also had less uptake of brain due to P-gp efflux which led to poor
bioavailability [187]. When incorporated in PLGA NPs, the brain up-
take efficacy of olanzapine loaded NPs increased by 6.35-fold for IV
administration and 10.86-fold after IN administration compared with
free drug solution. Md et al. further studied PLGA NPs for their brain
uptake efficiency. PLGA NPs were synthesized by solvent emulsification
diffusion-evaporation technique and in vitro and in vivo parameters
were evaluated. When donezepil was administered in PLGA NPs by
nasal route, brain uptake of drug by PLGA NPs was enhanced, sig-
nificantly, compared with free drug solution, as confirmed by the bio-
distribution studies [188]. PEG is another versatile polymer, as a better
choice for construction of NP for IN delivery, possessing mucus pene-
tration abilities. PEG-PLGA NPs constructed by coupling PEG with
PLGA and are useful tools to target the brain via nasal mucosal. Most
research is now focused on PEG-PLGA NPs and many protein molecules
are conjugated onto these NPs and studied for enhancement of IN drug
delivery for brain targeting. For example, lectins are proteins or gly-
coproteins that recognize and bind specific carbohydrates on the cell
surface and thereby improve attachment to the mucus and cilia. Lectin
could be bound to N-acetylglucosamine and sialic acid residues on the
nasal epithelial membrane. Researchers utilized this potential to con-
jugate it with PEG-PLGA NPs to improve IN transport to brain. Zhang
et al. conjugated PEG-PLGA NPs with Solanum tuberosum lectin (STL)
and entrapped fibroblast growth factor (I-bFGF) in it. Intranasally ad-
ministered modified NPs exhibited significantly higher area under the
concentration time curve (AUC) in different parts of the brain than IV
administered STL NPs and IN drug solution. Furthermore, Conjugated
nanocarriers improved memory function, as shown by water maze test.
These results revealed that STL conjugated PEG-PLGA NPs were pro-
mising DDSs for delivery of peptide and protein based drugs to brain via
nasal route [189]. PEG-PLA NPs could be functionalized with wheat
germ agglutinin (WGA) for transmembrane delivery of drugs. Liu et al.
explored pathways for delivery of WGA-NPs to brain after IN
375
Journal of Controlled Release 268 (2017) 364–389
Fig. 5. Comparison of florescent intensity of OL-NPs in brain region with unmodified NPs.
administration. They formulated PEG-PLA NPs and functionalized with
WGA. Coumarin was incorporated in NPs to track the florescent in-
tensity of NPs in various parts of the brain. WGA-NPs were transferred
to olfactory bulb via olfactory neural connection by transcellular me-
chanism. Trigeminal pathway played a role for transport of NPs to
caudal brain area, whereas transfer of NPs to brain via cerebrospinal
fluid was minimal [190]. Traditional lectins were immunogenic and
induced immune response therefore; newer lectins with less im-
munogenicity were needed to improve the delivery of NPs via nasal
route. Wen Z et al. conjugated odorranalectin (OL), smallest and less
immunogenic lectin, to PEG-PLGA NPs. To investigate the direct IN
transport of conjugated NP to brain, NPs were loaded with urocortin
peptide (UCN) and distribution to various regions of CNS was de-
termined. Surface modification of NPs with OL potentiated the level of
UCN in brain and enhanced the in vivo efficacy of UCN. Fluorescent
intensity of OL NPs in the brain region increased gradually within 8 h,
whereas it was decreased from 2 h afterwards for unmodified NPs
(Fig. 5), demonstrated enhanced uptake of OL NPs by the brain. It was
suggested that NPs might be transported to brain through olfactory
pathway due to binding of OL to L-focuse on the olfactory epithelium
[191]. From these studies, it was obvious that lectin conjugated NPs
protected peptide and protein based drugs from peptidase degradation
and improved their pharmacological activity, when administered in
animals for brain targeting via nasal route. Lactoferrin is another pro-
tein which could be conjugated onto PEG-PLGA NPs. Lactoferrin re-
ceptors are present on the respiratory epithelium cells and neurons
[192]. These receptors could be targeted by the lactoferrin conjugated
NPs for nasal drug delivery to brain. Recently, lactoferrin modified
PEG-PLGA NPs (Lf-NPs) were investigated to successfully deliver roti-
gotine to brain via nasal route for the treatment of Parkinson's disease.
It was reported that Lf-NPs delivered higher concentration of drug in
olfactory bulb, striatum and other brain regions compared to un-
modified NPs. These results declared that conjugation of PEG-PLGA NPs
with lactoferrin enhanced the delivery of rotigotine to brain via olfac-
tory and trigeminal pathway by interaction of lactoferrin with lacto-
ferrin-receptors [193].
Dendrimers are three dimensional polymers which are being uti-
lized to design NPs. NPs based on dendrimers have gained attention
now a day for transcellular and paracellular delivery of drugs and hence
better choice for IN brain targeting. While developing a drug for-
mulation, low aqueous solubility is a major concerning problem.
Dendrimers due to their unique structural characteristics enhance the
solubility by forming a drug complex. These nanocarriers have small
A.R. Khan et al.
size and positive charge which enable them to increase transmucosal
delivery and cellular uptake of drug. Polyamidoamine (PAMAM) den-
drimers were studied to enhance the aqueous solubility and improve
delivery of haloperidol to brain. Compared to intraperitoneal injection,
IN delivery resulted in significantly higher distribution of drug to brain
and plasma. 6.7 times lower doses of IN dendrimers produced same
behavioral response as induced by the intraperitoneal injection, in-
dicated the efficiency of dendrimers as potential IN DDSs to target the
brain [194]. PAMAM dendrimers had ability to deliver nucleotides and
nucleic acid to brain via nasal route. In this context, siRNA were at-
tached onto PAMAM dendrimers to target against high mobility group
box 1 (HMGB1). Upon IN administration, it was observed that siRNA
were distributed in different regions of brain and depleted the target
gene in peripheral cortex and striatum. Moreover, HMGBI siRNA de-
creased the infarct volume in brain when intranasally administered to
stroke induced rats. These positive findings potentiated the future role
of dendrimers for IN brain targeting [195]. In addition to therapeutic
potential, dendrimers also had diagnostic applications. Effects of
PAMAM dendrimers on neurological biomarkers in mouse brain via
nasal route were investigated. After 24 h of single dose of PAMAM
administration to mice, significant modification of level of gene ex-
pression related to brain derived neurotrophic factor signaling pathway
was observed. However, it was not clear whether these dendrimers
delivered to brain through systemic circulation or translocated via ol-
factory pathway by transcellular or paracelluler route [196].
4.2.1.2. Peptide surface modified NPs. Bioactive peptides such as cell-
penetrating peptides (CPPs) modify the surface of NPs and mediate
delivery of drugs across nasal mucosa. They promote transport of drugs
via olfactory pathway to brain. Among CPPs, low molecular weight
376
Journal of Controlled Release 268 (2017) 364–389
Fig. 6. Pictorial representation of nanoformulations for
nose to brain drug delivery.
protamine (LMWP) is therapeutically important in transmucosal
delivery of attached molecules. LMWP is not antigenic or mutagenic
and exhibits low toxicity, thus safer than protamine. The LMWP-CPPs
could be utilized to enhance IN transport of proteins to brain. It was
studied that conjugates of LMWP–proteins were effectively penetrated
into the brain by noninvasive IN administration. To strengthen this
concept, LMWP was conjugated with bovine serum albumin (BSA,
Sigma–Aldrich) protein and administered intranasally to mice. In vivo
imaging had shown that LWMP-protein conjugate was significantly
distributed to olfactory bulb and brain tissues. Absorption of drug to the
systemic circulation and distribution in major organs was very less. This
study concluded that LWMP opened the tight junction of nasal
epithelial cells and promoted neural transport to brain [197]. LWMP
could be functionalized onto the surface of drug loaded NPs. CPP
surface modified NPs provide safe and effective noninvasive delivery of
drugs to brain. PEG-PLA NPs were conjugated with LWMP through
maleimide linkage and incorporated with coumarin to determine their
brain uptake efficiency. Cellular uptake studies had shown that level of
modified NPs in the cells was significantly higher than unmodified NPs.
In vivo experiments in rats revealed that conjugation of NPs with
MWMP enhanced the transport of NPs to brain as confirmed by the
microscopic data. It was investigated that coumarin loaded LWMP NPs
after IN administration were effectively delivered to brain along both
olfactory and trigeminal pathways [198]. CPP surface modified NPs
might be helpful for future development of peptides and proteins based
products to target the brain through nasal delivery. Potential of
macromolecular drugs in neuroprotective therapy by IN
administration is limited due to low nasal absorption. Co-
administration of macromolecular drugs with CPPs potentiates their
IN transport to brain. Insulin was co-administered with Penetratin, a
A.R. Khan et al.
CPP, to the rats and its distribution in different brain regions was
measured. Insulin was found in distal brain regions including cerebral
cortex, cerebellum and brain stem without systemic exposure [199].
Enhancement of IN macromolecular drug delivery to brain through
peptide surface modified NPs is another useful approach. CPP modified
PLGA NPs were fabricated and evaluated for IN delivery of insulin to
treat the Alzheimer's disease. In vivo studies demonstrated that peptide
modified NPs effectively delivered insulin to brain with total brain
delivery efficiency of 6% [200].
4.2.1.3. Lipid based NPs. In addition to polymeric NPs, lipid based NPs
are also important for rapid IN transport of drug to brain. Solid lipids
NPs (SLNs) are biodegradable, biocompatible and have no toxicity on
nasal mucosa. These NPs have controlled release properties and
increase the stability of encapsulated drugs. In this context,
hydrophilic drug rivastigmine (RHT) loaded SLNs were studied using
quality by design (QbD) approach for IN administration. SLNs were
designed by homogenization and ultrasonication technique using lipids,
surfactant and stabilizers. Ex-vivo permeation studies indicated that
RHT SLNs showed higher drug diffusion compared to drug solution.
RHT SLNs were safer for delivery of drugs to nasal mucosa as no
nasocilliary damage and/or cell necrosis were observed [201].
Similarly, phospholipid-based gelatins NPs (GNLs) were compared
with gelatin NPs (GNs) for IN delivery of basic fibroblast growth
factor (bFGF) to brain. The GNLs with particle size 143 ± 1.14 nm and
Zeta potential − 38.2 ± 1.2 mV showed better profile than GNs. The
level of bFGF was significantly increased in olfactory bulb and striatum
by the IN administration of bFGF-GNLs. Compared to bFGF-GNs, more
bFGF-GNLs were found in the striatum without causing damage to nasal
mucosa. These results depicted that NPs were transported through
olfactory pathway and released the drug in striatum. Thus, GNLs were
efficient for delivery of macromolecular drug to brain through direct
nasal pathway without causing toxicity [202].
Nanostructured lipid carriers (NLCs) are also lipid based NPs con-
taining liquid lipid in addition to solid lipid contents. NLCs overcome
the entrapment efficiency and storage related problems of SLNs. In
NLCs, liquid lipid contents improve the drug loading capacity by
creating imperfect structure within the lipid matrix. Likewise SLNs,
these nanocarriers also have sustained release properties [203]. For
efficient IN delivery of Ondansetron hydrochloride (OND) to brain,
Devkar et al. investigated mucoadhesive NLCs. NLCs were formulated
using Delonix regia gum as a mucoadhesive polymer and administered
intranasally and intravenously to the rats. Compared to IV administered
NLCs, IN NLCs had shown higher drug targeting efficiency and direct
transport percentage. It was observed that mucoadhesive NLCs pro-
moted absorption and enhanced residence time of OND in the nasal
cavity, resulted in optimized transport to CNS. These NLCs delivered
OND to brain through olfactory neural connection via transcellular
mechanism [204]. New technology is needed to enhance the brain
uptake of intranasally delivered peptides without degradation by nasal
peptidase. For this purpose, chitosan coated NLCs (CS-NLCs) were de-
signed and investigated for IN administration of proteins to brain. The
resultant nanocarriers were biocompatible and no cellular toxicity was
appeared in the nasal mucosa of mice. Higher accumulation of CS-NLCS
in the cerebral cortex than in the cerebellum and hippocampus in-
dicated that nanocarriers were transported through olfactory and tri-
geminal pathway [205].
4.2.2. Nanoemulsions
Recently, animal studies have shown that nanoemulsions enhanced
the permeability across nasal epithelial cells and promoted nasal de-
livery of small molecular weight hydrophobic drugs to brain. For ex-
ample, IN delivery system of cyclosporine-A (CsA) based on Oil-in-
water nanoemulsion was fabricated and studied. Upon IN and IV ad-
ministration of nanoemulsion (CsA-NE) and solution (CsA-s) of CsA to
the Sprague–Dawley rats, it was observed that IN CsA-NE resulted in
377
Journal of Controlled Release 268 (2017) 364–389
highest brain accumulation compared to IN solution and IV adminis-
tered CsA-NE. The brain/blood ratio was also highest for CsA-NE and
CsA-NE reduced the major organ exposure. These observations in-
dicated that CsA-NE was capable of directing nose-to-brain transport
without systemic absorption [206]. Similarly, water in oil NE loaded
with Ginsenoside, basic component of Panax notoginseng saponins
(PNS), was investigated for direct IN transport to brain. IN delivery of
NE exhibited higher level of drug in the brain than orally administered
PNS. The values of percentage of drug targeting efficiency (%DTE) and
direct transport percentage (%DTP) were also higher for IN NE. The
author concluded that NE is preferred DDS to target the brain via nasal
pathway [207]. Many studies have been conducted to evaluate the ef-
fect of mucoadhesive agents on NE for direct nose to brain drug de-
livery. Sood et al. optimized the poorly soluble curcumin loaded NE
using chitosan as mucoadhesive agent. Different concentrations of oil,
surfactant and co-surfactant were used to construct nanocarriers. They
investigated that mucoadhesive NE was highly diffused across sheep
nasal mucosa compared to curcumin solution. Additionally, NE resulted
in higher release compared to the control and no ciliotoxicity was ob-
served, indicated that mucoadhesive NE formulation was safer and ef-
ficient for direct IN delivery of drug to brain [208]. Future prospect of
NE in nasal drug delivery is to deliver genes and nucleotides to treat
neuronal disorders. In this connection, NEs incorporating anti-TNFα
siRNA were evaluated for their therapeutic potential in the treatment of
neuroinflammatory disorders. SiRNA was complexed with cationic NE
of omega-3 fatty acids and investigated for down regulation of target
gene in the CNS. IN administration of these NEs demonstrated en-
hanced uptake of siRNA in brain compared to uptake by the blood. Non-
viral cationic lipid based NEs efficiently knocked down the TNFα gene
transcript levels in lipopolysaccharide -stimulated macrophages. It was
concluded that cationic NEs protected nucleic acid from enzymatic
degradation, enhanced its exposure to nasal mucosa and directly de-
livered to brain to down regulate TNFα in experimental neuroin-
flammation [209]. Amyotrophic Lateral Sclerosis is another neurode-
generative disease and riluzole is the only drug available for its
treatment. Riluzole belongs to biopharmaceutical class II system has
low bioavailability and hence its therapeutic potential is lost. NE was
explored to improve the delivery of riluzole to brain. NE was prepared
by titration method using sefsol, tween 80 and carbitol. IN adminis-
tration of drug loaded NE demonstrated, significantly, enhanced brain
uptake than orally administered NE in rats without causing nasal ci-
liotoxicity [210].
4.2.3. Micelles
Polymeric micelles as block copolymers are most promising drug
delivery platforms to enhance the delivery of drugs and genes vial nasal
rout to brain. These are nanoscale drug carriers with ability to in-
corporate wide range of drugs including protein based drugs. A study
was conducted to investigate micellar nanocarriers for the efficient
delivery of zolmitriptan to brain. It was observed that nanocarriers
were transported to brain in significantly higher concentration com-
pared to IN and IV administered solution of zolmitriptan. The micellar
formulation was delivered to olfactory bulb through olfactory and tri-
geminal pathway but to midbrain and cerebellum, nanocarriers were
transported by trigeminal pathway only [211]. CPP-modified block
copolymer micelles as IN DDSs for brain targeting were studied. TAT
conjugated amphiphillic block copolymers were constructed and loaded
with coumarin for biodistribution studies. CPP conjugated methoxy
poly (ethylene glycol) (MPEG)/poly (caprolactone) (PCL) micelles ex-
hibited higher cell uptake compared with unmodified micelles and
distribution to peripheral organs was also less. These observations de-
clared that IN administration of CCP conjugated micelles followed di-
rect neural transport to CNS without absorption into blood and dis-
tribution to peripheral organs [212]. Newer drug delivery technologies
in clinical and pharmaceutical fields are of the great interest for effi-
cient transport of nucleotides to brain. To enhance the therapeutic
A.R. Khan et al.
efficacy of small interfering RNA (siRNA), while treating the brain
disorders, Kanazawa et al. explored the neural connection between nose
and brain. They loaded MPEG-PCL-Tat micelles with siRNA and eval-
uated for their brain uptake efficiency. Compared to intravenous de-
livery, intranasally delivered MPEG-PCL-Tat significantly enhanced the
nucleic acid concentration in brain. These modified micelles utilized
both olfactory and trigeminal nerve pathways. The distribution of nu-
cleic acid to rostral brain tissue was the result of olfactory transport,
whereas in caudal brain tissue and brainstem nucleic acid was trans-
ported by trigeminal connection [213]. Similarly, potential of MPEG-
PCL-TAT micelles in brain tumor therapy was investigated. Camp-
tothecin (CPT), an anticancer drug, was encapsulated in TAT-modified
micelles and administered intranasally to the rat. Compared to un-
modified micelles, TAT-modified micelles significantly increased
median survival time of rats bearing intracranial glioma tumors. CPT
loaded MPEG-PCL-TAT had shown higher cellular accumulation due to
interaction with c6 cells and inhibited the tumor growth [214]. These
findings were big hope for gene therapy, brain tumors and neu-
ropsychiatric disorders.
4.2.4. Nanogels
To enhance the deposition of drug at nasal epithelium by increasing
the viscosity is a versatile approach to improve IN delivery of drug to
brain. Gels with three dimensional structure increase the residence time
in nasal cavity by increasing the viscosity, favor nasal delivery to brain.
Naratriptan hydrochloride is effective against migraine headache but
frequent doses are required due to hepatic metabolism and low bioa-
vailability. It was reported that direct IN delivery to brain by thermo-
reversible gel overcame the bioavailability related problems of nara-
triptan. Poloxamer 407 based thermoreversible Nanogels were
constructed using Carbopol 934 to confer mucoadhesive properties.
Researchers investigated that release of drug from gel was delayed and
dependent on the concentration of Carbopol. Histopathological studies
confirmed safety profile of nanoformulations [215]. siRNA den-
driplexes loaded in situ-forming mucoadhesive gel formulations were
tested for IN brain targeting. In situ forming gels were constructed by
blending thermosensitive poloxamer with mucoadhesive chitosan or
Carbopol and loaded with siRNA dendriplexes. It was observed that IN
dendriplexes in gel delivered, significantly, higher amount of radio-
activity to the brain than IV administered dendriplexes and IN naked
siRNA within gel. In situ gel maintained the stabilize structure of dex-
driplexes and enhanced their uptake by olfactory neurons. The author
concluded that finding of radioactivity in the brain could not lead to
assume the presence of intact siRNA molecules or siRNA dendriplexes
in the brain. However, it was first time reported that in situ forming
mucoadhesive gel enhanced the IN delivery of radioactive nucleotide to
the brain [216]. In situ gel formulation consisting of resveratrol nano-
particulates and an ionic-triggered deacetylated gellan gum (DGG)
matrix for direct IN delivery to brain was studied. The markedly in-
creased concentration of resveratrol in the brain by in situ gel for-
mulation demonstrated direct nose to brain transport. This combined
formulation of nanosuspensions and the DGG in situ gel solution with
properties of both nanoparticles and ionic sensitive gel overcame the
bioavailability related problems of conventional nasal drops. In con-
clusion, this composite system enhanced the permeability of nasal
mucosa and increased residence time in nasal cavity [217]. Khan et al.
incorporated ropinirole, a dopamine D2 agonist in chitosan and hy-
droxyl propyl methyl cellulose gel. Compared to IV administration,
these gel on IN administration resulted in 8.5 time higher concentration
in brain and 3 times higher than intranasally administered ropinirole
solution [218]. Polymeric gel suspensions using PEG, Carbopol and
carboxymethyl cellulose were designed and evaluated for IN delivery of
melatonin. 6.77- and 9.22-fold increased brain levels of drug by CMC
and carbopol suspension, respectively, than IV drug solution were
found. Microdialysis studies showed that polymeric gel suspensions
delivered melatonin to brain through olfactory pathway [219].
378
Journal of Controlled Release 268 (2017) 364–389
4.2.5. Liposomes
Liposomes, as a drug delivery carrier, have been studied for more
than 30 years [220,221]. In recent years, liposomes are under rapid
development to target the brain by nasal route of administration. Li-
posomes encapsulate proteins, improve their lipophilic characteristics,
prevent enzymatic degradation and increase uptake by the cells. Fur-
ther, cationic liposomes increase residence time in the nasal cavity and
promote transport of proteins across nasal mucosa. H102 peptide-
loaded liposomes were tested on Calu-3 cell monolayers for IN brain
delivery to treat Alzheimer's disease. AUC of H102 liposomes in the
hippocampus was 2.92-fold larger than that of H102 solution. H102
might be delivered by olfactory pathway or trigeminal pathway to
brain. Improved memory function at lower doses of peptide liposomes
was reflected by the increased concentration of peptide in hippocampus
[222]. Surface modified liposomes for delivery of risperidone to brain
via nasal route were studied by Narayan et al. Risperidone loaded li-
posomes were synthesized using thin film hydration method and sur-
face was modified with stearylamine and MPEG-DSPE for efficient pe-
netration to brain. Stearylamine liposomes prolonged the release of
drug whereas; PEGylated liposomes improved bioavailability and
showed higher mean residential time than conventional formulations.
IN liposomes delivered, significantly, higher concentration of drug to
brain compared to IV bolus injection of drug. High value of BTE index
indicated that PEGylated liposomes were directly transported to brain
bypassing the BBB. However author suggested conducting further pre-
clinical and clinical studies in larger group to evaluate these results are
necessary [223]. Similarly, xanthan gum coated mucoadhesive lipo-
somes for delivery of curcumin were prepared and administered via
nasal route. The liposomes showed higher drug distribution (1240 ng)
in brain compared to drug solution (65 ng). However mechanism of
drug transport to brain was not studied [224]. To improve rivastigmine
distribution in brain and enhance pharmacodynamics, intranasally ad-
ministered rivastigmine liposomes (Lp) and CPP modified liposomes
(CPP-Lp) were optimized. Intranasally administered rivastigmine lipo-
somes enhanced distribution of drug to brain and retained the drug for
adequate time. In addition, there was very mild nasal toxicity of lipo-
somal formulations. Liposomes especially CPP-Lp improved pharma-
codynamic profile of rivastigmine delivered via olfactory pathway to
brain [225].
4.2.6. Nanoemulsomes
Nanoemulsomes are nanocarriers with solid fat cores surrounded by
phospholipids bilayer and stabilized by cholesterol and soya lecithin
[226]. They are lipid based DDSs with properties of liposomes and
emulsions [227] and are better choice for delivery of poorly soluble
drugs. Emulsomes due to unique properties and smaller size were ex-
plored for IN drug delivery to brain [228]. To avoid peripheral toxicity
of orally administered oxcarbazepine (OX), emulsomes of OX were
studied as nanocarriers for IN brain targeting. Emulsomes were pre-
pared using different triglycerides cores in different ratios and soya
phosphatidylcholine and administered intranasally to the rats. The
higher value of AUC, %DTP and %DTE for emulsomes than IV ad-
ministered drug solution and oral product indicated direct nose to brain
transport of emulsomes via olfactory pathway. Pharmacokinetic studies
revealed that emulsomes delivered drug both through direct nasal
transport and systemic delivery of drug from nasal mucosa to brain
[229]. Another study was conducted to compare the emulsomes of OX
with emulsomes cryo-and-themogels, aimed to deliver nanocarriers for
brain targeting. Poly ethylene glycol diacrylate (PEGDA) cryogels were
fabricated with varying concentration of PEGDA and emulsomes were
sequestered in gels. Similarly, thermoreversible thermosensitive PLGA-
PEG-PLGA triblock copolymer was synthesized and emulsomes were
sequestered in thermogel. After IN administration it was observed that
emulsomes had shown highest drug targeting efficiency and direct nose
to brain transport and delivered, significantly, higher concentration of
OX in brain than cryo-and-themogels. Emulsomal cryo-and-themogels
A.R. Khan et al.
transported drug through systemic delivery with minimum involvement
of direct transport to brain but in case of emulsomes, direct transport
prevailed. The aim of IN delivery is to target the brain through tri-
geminal or olfactory pathway and to limit systemic exposure of drug.
Hence, more studies are required to investigate emulsomes for targeting
the brain through nasal route without absorption through respiratory
epithelium.
4.3. Microcarriers as DDS
Besides nanocarriers, microspheres could also be suitable candi-
dates for direct nose to brain targeting via integrated nerve pathways.
Mucoadhesive microspheres were investigated for brain targeted de-
livery of zolmitriptan via nasal route. Mucoadhesive IN formulations
based on chitosan glutamate and hydroxypropyl methylcellulose
(HPMC) were designed and compared with IV infusion and nasal aqu-
eous suspension of drugs for their brain uptake efficiency. Compared to
IV and oral administration, intranasally administered suspension pro-
duced CNS effects with lower peripheral toxicity. Chitosan glutamate
microcarriers showed highest brain uptake efficiency than HPMC mi-
crocarriers and nasal suspension of drug. Chitosan delivered drug
through permeation enhancement mechanism across the olfactory
mucosa. These microspheres exhibited less exposure of drug to per-
iphery as a result of direct transport of drug to the CNS [230]. Defer-
oxamine (DFO) has diverse neuroprotective effects and direct brain
targeting of DFO could be beneficial for the treatment of central ner-
vous system disorders related to iron dysregulation such as Hunting-
ton's disease [231,232], Alzheimer's disease [233] and Parkinson's
disease [234]. Rassu et al. investigated intranasally administered
spherical chitosan chloride and methyl-β-Cyclodextrins microparticles
loaded with DFO for nose to brain permeation. Microparticles were
prepared via spray drying and compared with nasally administered free
drug solution. These carriers were rapidly delivered to cerebrospinal
fluid (CSF) and CNS in rats, whereas no drug CSF uptake of DFO water
solution was detected. Moreover, cyclodextrins based microparticles
regarding delivery of drug through olfactory mucosa were superior to
chitosan microparticles. These results suggested direct IN delivery of
encapsulated DFO to brain [235]. A study was conducted to evaluate
noninvasive transport of midazolam microspheres into CSF via in-
tegrated nerve pathway. Gelatin-chitosan based mucoadhesive micro-
spheres were designed and administered intranasally to the rats. Mid-
azolam microspheres had shown significantly higher level in CSF than
IV administered midazolam solution. Drug toxicity index and drug
targeting percentage indicated direct transport of drug loaded micro-
spheres to CSF [236]. Similarly, Jose et al. studied the effect of gel on
the release characteristics of microspheres. They formulated thermo-
sensitive gel using puluronics and loaded with mucoadhesive micro-
spheres. Chitosan microspheres loaded thermosensitive poloxamer-
based gel when administered intranasally to the rats, provided sus-
tained release of lorazepam over a time period of 24 h, whereas lor-
azepam microspheres in PBS (pH 6.2) and lorazepam powder loaded in
poloxamer gels released drug over 9 and 15 h, respectively. These re-
sults suggested that loading of microspheres in a gel enhanced the re-
sidence time of drug in nasal epithelium and hence beneficial for drug
delivery to CNS through nasal mucosa [237].
4.4. Diagnostic applications of IN nanocarriers
Development in nanotechnology led the focus of scientists in de-
signing and exploring potential of NPs in diagnosis and treatment of
brain disorders. Mostly IN nanoformulations were designed for ther-
apeutic purposes. The therapeutic nanocarriers were aimed to transport
drug at targeted site in the brain without accumulation to nontargeted
tissues. Recently, nanocarriers are designed for dual purposes; single
nanocarrier has diagnostic and therapeutic applications. Dendrimers
are the nanocarriers have diagnostic applications along with
379
Journal of Controlled Release 268 (2017) 364–389
therapeutic potential. Effects of PAMAM dendrimers on neurological
biomarkers in mouse brain via nasal route were investigated. After 24 h
of single dose of PAMAM administration to mice, significant mod-
ification of level of gene expression related to brain derived neuro-
trophic factor signaling pathway was observed. However, it was not
clear whether these dendrimers delivered to brain through systemic
circulation or translocated via olfactory pathway by transcellular or
paracelluler route [192]. NPs carrying image guiding agents have been
introduced for nose to brain delivery. Curcumin is obtained from
naturally occurring plant Curcuma longa and acts as florescent marker in
Alzheimer's disease. It has binding affinity with Aβ peptide and de-
creases aggregation of Aβ. Liposomes were constructed containing
curcumin. Postmortem studies shown significant deposition of labeled
Aβ peptide in brain tissues of Alzheimer's patient [250]. Rhodamine is
another florescent marker and biodistribution studies of NPs carrying
rhodamine were conducted. Positively charged chitosan NPs and ne-
gatively charged PLGA NPs were constructed and administered in-
tranasally in animals. Negative NPs shown florescence at early time
point and strong florescence of positive NPs after 48 h were detected.
Rhodamine had shown florescence in different parts of the brain and is
useful to detect distribution of NPs in brain [251]. Fluorescein is used to
determine the pathway of nanocarriers' transportation after IN admin-
isteration. Fluorescein labeled dextran (FD3) IN solution was adminis-
tered to the rats. Fluorescence in the olfactory epithelium and olfactory
bulb was detected within 15 min [252]. Polymeric micelles based on
MPEG-PCL were designed and loaded with coumarin (fluoroscein
model drug). After IN administration in rats, biodistribution in brain
using fluorescent microscopy was studied. Coumarin concentration was
used as florescent marker and smaller size micelles delivered more
concentration of coumarin than larger size micelles [253].
4.5. Toxicological studies of nanocarriers
Various polymeric formulations for nose to brain delivery were
accessed for toxicity. Mostly polymeric nanoconstructs have cationic
polymers such as chitosan and PEG. Cationic polymers have interaction
with negatively charged surface of mucosal membrane and cause
toxicity. Negatively charged carriers are repelled by the cell membrane
result in low uptake and unsuitable for transmucosal delivery. A study
was conducted to evaluate pharmacokinetic, toxicity and safety profile
of chitosan solution. Toxicity of chitosan was related to deacetylation
degree and not depends on molecular weight of chitosan [254]. In vitro
and in vivo studies represented cytocompatibility of chitosan. In-
tranasally administered chitosan formulations (0.25% w/v) to guinea
pigs for 28 day [255] and single dose of 0.125%, 0.25% and 1% chit-
osan hydrochloride to rats had shown no observable toxicity to nasal
tissues [256]. Similarly intranasally administered chitosan solution for
4 days was safe and had not shown any sign of apoptosis of glial cells,
inflammatory infiltrates or glial scars [257]. Microemulsion formula-
tions were investigated for toxicological screening in rats. Nasal mucosa
and cartilage were found to maintain their normal histological structure
and no cytopathological abnormalities were reported [258].
Polymeric and lipid based nanovehicles are widely used for nose to
brain targeting and toxicity profile of NPs should be evaluated for de-
ciding about risks associated with attractive drug delivery. NPs sus-
pensions resulted in higher cell viability than polymeric solution. NPs
had shown concentration dependent viability of Calu-3 cells. NPs
augmented local inflammation of nasal mucosal membrane without
appearance of systemic inflammatory response [259]. NPs cross olfac-
tory epithelium and reach different brain regions. Md and collaborators
administered BRC loaded NPs in mice and examined brain for toxicity.
There was no difference of treated brain with normal brain. Smaller size
and few eosinophilic lesions were found than mice treated with halo-
peridol [260]. Lectins are considered to be toxic to the mammalian cells
and induce nasal ciliotoxicity and oxidative stress. WGA conjugated
PEG-PLA NPs were constructed via maleimide linkage and loaded with
A.R. Khan et al.
coumarin for IN administration. WGA-NPs and unconjugated NPs ex-
hibited negligible ciliotoxicity [261]. Tat-mediated nose-to-brain de-
livery may induce cargo-dependent cytotoxicity [262]. LMWP, which is
claimed to be non-cytotoxic, may still harm the normal tissue due to its
lack of cell type selectivity [263].
Micellar nanocarriers based on PEG were designed and incorporated
with zolmitriptan. Toxicological studies of intranasally administered
micelles for 28 days were performed and no toxicity was found [264].
IN Pluronic based block copolymer micelles loaded with olanzapine
were formulated and investigated for toxicological studies. Ex vivo
toxicological analysis in sheep nasal mucosa reported minor histo-
pathological changes in nasal mucosa [265]. siRNA dendriplexes loaded
in situ-forming mucoadhesive gel formulations were tested for IN brain
targeting. In situ forming gels were constructed by blending thermo-
sensitive poloxamer with mucoadhesive chitosan or Carbopol and
loaded with siRNA dendriplexes. It was observed that IN dendriplexes
in gel had not shown any toxicity [216]. Liposomes are consist of
naturally occurring lipids and thought to be nontoxic. Liposomes for
intranasal brain delivery were examined for toxicological screening.
Liposomes encapsulating quetiapine were formulated via thin film hy-
dration method and diffusion across sheep nasal mucosa was observed.
Ciliotoxicity studies reported no histopathological changes with lipo-
somal delivery in nasal mucosa whereas, isopropyl alcohol, positive
control, damaged nasal epithelium and deep tissues alongwith necrosis
[266]. Few studies were published regarding toxicity of microparticles
constructed for nose to brain delivery. Ex vivo studies of microspheres
imbibed in gels in bovine nasal tissues were conducted and signs of
toxicity in bovine tissues were reported [267].
5. Nasal drug delivery devices for brain targeting
In addition to DDSs, another strategy for direct transport of drug
from nose to brain is to deposit the drug on olfactory epithelium or
region of nose innervated by trigeminal nerves so that more drug is
transported to brain via olfactory/trigeminal pathway. For this purpose,
many effective and efficient novel nasal drug delivery devices were
studied by the researchers and some were patented. Among these de-
vices, pressurized olfactory delivery devices, nebulizers, atomizers,
pressurized meter dose inhalers and Breathe Powered Bi-directional
nasal devices gained access in the clinical settings Table 6. Nasal drug
delivery devices were categorized into three classes, liquid, powder and
semisolid formulations containing devices for brain targeted devices.
5.1. Powder devices
Powder based formulations are more suitable for IN drug delivery.
Powder particles are not easily dissolved in the nasal mucosa and re-
mained in contact with mucosa for long period of time. Powder dosage
forms are free from preservatives, enable large doses of drug adminis-
tration, prevent microbial contamination and improve patient com-
pliance, made them potential candidates for nasal delivery. Powder
formulations of macromolecular drugs such as peptide and non peptide-
Table 6
FDA approved products based on nasal drug delivery device.
Name of product Pharmaceutical firm Type of delivery device
Merck's Nasonex® Apotex Inc. Nasal spray
Advancia® Nemera Multidose Nasal spray pump
Narcan® Adapt Pharma nasal spray
Onzetra™ Xsail™ Optinose Inc. Breath Powered Delivery Device
Dymista® Meda Pharmaceuticals Inc. Nasal spray
Astelin® Meda Pharmaceuticals Inc. Nasal spray
Zomig® AstraZeneca Pharamaceuticals Nasal spray
Rhinocort® McNeil Consumer Healthcare Nasal spray
Triamist® Cipla Medpro Metered spray
380
Journal of Controlled Release 268 (2017) 364–389
based drugs have been designed and successfully investigated for nasal
delivery. Metered dose insufflators containing mucoadhesive powder
polymers delivered polymers in nasal cavity. Polymers formed thick gel
on contact with mucosa and decreased mucociliary clearance.
5.1.1. Insufflators/syringe with tube
Insufflator consists of straw or tube containing drugs and connected
with syringe. This device directly delivers drugs to the olfactory region
in the absence of pathological condition. Rhinologist examines olfac-
tory region located beyond the nasal valve before insufflations. Local
anesthetics or decongestants are applied before insufflations facilitate
delivery to olfactory region. Devices fall in this category are described
below.
5.1.1.1. Trimel/direct haler™. Direct Haler, Danish company, designed a
device to deliver very fine particles into nasal cavity with lungs
exposure. This prefilled, pre-metered disposable device is unit or
bidose system, proved tolerability and acceptability in clinical
studies. Trimel device has benefit of utilizing patients own exhalation
force for convenient delivery. One end of the tube is inserted in nasal
vestibule and patient blows in the other end. Corrugations in the mid of
the device provides flexion and turbulence to spread the particles.
Patient exhalation force expels the particles from the tube to the nostril.
Rhynal catheter elevates soft palate and the nasal cavity is isolated from
the rest of respiratory system, avoiding respiratory deposition. After
successful delivery, nasal and oral passages retain their normal
functions. Many complications are associated with commonly used
liquid drops, sprays and inhaler such as chance of liquid dose to come
out of nose after delivery [268], swallowing of drug after delivery may
lead to bitter taste and poor mucosal penetration [269], necessity of
preservatives in multidose containers results in unacceptability to
patient and need of priming. Direct haler devices overcome these
problems. Direct Haler device is free from contamination and
ultimately preservatives. It is free from priming and cleaning.
Pressurized metered dose inhalers (pMDI) have poor patient
acceptability due to “cold-blow” and “hard-blow” of medication from
inhaler but trimol utilized patient own exhalation force at normal
temperature and preferred over pMDI. The current focus of Direct Haler
is nose to brain delivery, demands drug targeting beyond the nasal
valve. Smaller particles below 5 μ are required for olfactory deposition.
Reduction of particle size increases chance of drug deposition to lungs.
Scientists are now working to find a new delivery method for successful
olfactory delivery without lungs exposure. Bi-dose device deliver two
doses, one in each nostril. Direct Haler Nasal devices can be “clicked”
together to constitute such a compact bi-dose. In addition, firm has
designed special caps to keep contents with different sensitivity to
humidity and temperature. These devices are cost effective and easy to
manufacture. Manufacturing process resembles drug capsule design.
Device comprises of tube and cap. Tube is manufactured using
extrusion and roll forming technique, whereas cap is designed by
injection molding. Powdered drug is filled in tube with high speed
capsule filling machine. Simplicity and straightforward manufacturing
Active ingredients Disease
Mometasone furoate monohydrate Nasal congestion
Corticosteroid Allergic rhinitis
Naloxone hydrochloride Opoid overdose
Sumatriptan nasal powder Migraine
Azelastine hydrochloride/fluticasone propionate Seasonal allergic rhinitis
Azelastine hydrochloride Seasonal allergic rhinitis
Zolmitriptan Acute migraine
Budesonide Nasal congestion
Triamcinolone acetonide. Allergic rhinitis
A.R. Khan et al.
process make this device attractive for future delivery of combination
therapy.
5.1.1.2. Breathe Powered Bi-Directional ™ technology. Bi-Directional
Breath Powered drug delivery technology exploits the normal breath
process of the body to deposit the drug on nasal epithelium [270]. This
Bi-Directional™ technology could be utilized to any type of dispersion
technologies related to liquid and powder. When delivery of drug is
required, a user exhaled into the mouthpiece of device, soft palate is
elevated and the nasal cavity is isolated from the rest of respiratory
system. The patient exhaled force emitted the medication from device
into nostril while closure of the soft palate prevented the entry of drug
to the lungs. Expended nasal passage delivered medication deep into
the targeted area of the nasal cavity. When medicine is delivered to the
targeted sites, air following “Bi-Directional™ flow path” flowed around
to the opposite side of the nasal cavity and exit through the other side of
the nose rather than into the throat or lungs, as depicted in Fig. 7
[271,272]. Nasal valve is a narrow opening in the nasal cavity, created
a barrier for delivery of drug to brain. Neural connection to brain is
located posterior to this valve. Traditional nasal devices deliver drug in
or anterior to this valve. Optinose is a biopharmaceutical company,
patented closed-palate Bi-Directional™ Breath Powered® DDSs. This
technology used exhale device to target the drug to upper posterior part
of the nasal cavity, beyond this valve [272]. Role of oxytocin has
already been explored in the treatment of autism spectrum. Higher
doses of oxytocin are required for IN spray delivery, led to adverse
effects. Bidirectional technology is highly effective for IN delivery of
powder form of oxytocin in small doses. In this regard, a randomized
four-way crossover trial was conducted by Quintana et al. to study the
dose dependent effect of oxytocin on social cognition using Breath
Powered Optinose device (OPN). Oxytocin (OT) was delivered with an
Optinose exhaler device to healthy volunteers and direct nose to brain
transport activity of OT was studied. Although, similar plasma
concentration was achieved with IV administered and OPN delivered
OT but specific social-cognitive response was observed with OPN
delivered OT, indicated OPN directly transported drug across nasal
mucosa to brain utilizing neural connection. Moreover, a lower dose of
OPN-OT was more efficacious than higher dose of OPN-OT in producing
cognitive response, as previously reported [273]. Research Council of
Norway has granted USD $1.8 million to OptiNose AS, Norwegian
affiliate of OptiNose Inc., to study IN efficacy of Orexin-A in the
treatment of narcolepsy using OptiNose Bi-Directional Breath Powered
delivery technology [274]. Optinose devices are highly versatile in
delivering wide range of therapeutics (from small molecules to
vaccines) to brain. Single device could be used for multiple dosing.
381
Journal of Controlled Release 268 (2017) 364–389
Fig. 7. Cross sectional view of human nose with normal
dimension during soft palate elevation and bidirectional
flow of the air with Bi-Directional™ device.
Reproduced from [270].
5.1.2. Dry powder inhaler
Dry powder inhalers (DPI) enable powdered drug delivery via nasal
route. They are single use devices containing drug particles suspended
or dissolved in propellant or drug is dissolved when come in contact
with nasal mucosa. Very small doses in milligram are delivered to avoid
cough associated with large size particles. Unit and multi-dose powder
inhalers ensure accurate dosing of drug. Mono-dose inhaler resembles
single unit syringe. DPIs are used in asthmatic, bronchitis, COPD pa-
tients and also effective in the therapy of diabetes mellitus. Patients
hold mouthpiece in the mouth after actuation. Patients inhale deeply
and hold breath for 5–10s. Teijin Puvlizer Rhinocort® is oldest dry
powder inhaler and available in the world market. Rhinocort
Turbohaler®, Rhinicort Puvlizer ® and Erizas® are three nasal dry
powder based inhalers available for local treatment of rhinitis [275].
Rhinocort use capsule filled device and Erizas use multidose device
activated by the patient's breath. Pulvizer works on the airflow gener-
ated by the squeeze bottle or patient activated pump. It consists of
capsule inserted stem and lower body is soft plastic bulb. Body is
pressed to generate air blow, forces the powder particles to expel from
capsule into nasal cavity through stem. Eight inhalations are required to
empty the capsule [275]. DPI should deliver constant amount of drug to
the airstream that depends on total contents in container and discharge
during exhalation. DPIs are cheap and compatible with MDI. They have
commercial access to capsule filing equipments and availability of
novel technology to formulate dry powder form of potent drugs. DPIs
are not effective for high doses due to cohesive forces between particles.
Twin caps are DPI devices suitable for delivering high doses and chronic
dosing. It has simple design and automatically operating without
medical supervision especially in emergency conditions. It has two
capsule shaped cavities filled with dose range from μg to mg.
5.1.3. Nasal powder sprayers
Shin Nippon Biomedical Laboratories designed novel drug delivery
technology, μco™ System, based on mucoadhesive powder drug carrier.
μco™ Carrier technology promotes drug absorption and Fit Lizer is nasal
device for dry powder formulation delivery. μco™ Carriers increase
drug absorption, decrease dose requirement and provide quick onset of
action. It could be applied for local and systemic delivery, low mole-
cular weight and high molecular weight drugs. It works without ab-
sorption enhancers and proven safety in clinical trials. Powder carriers
prolong contact time with mucosa and enhance drug absorption [276].
Fit-lizer is patient operated device for delivery of dry powder for-
mulations. In multiple-use capsule device, single dose capsule is loaded
at each use and alternative to multiple dose capsules of DPI for therapy
of chronic diseases. Capsule chamber is pulled to open and filled with
A.R. Khan et al.
capsule and chamber is closed. Pump is squeezed and air blown through
capsule delivered the drug. Portable and light weight single use device
is effective technology for acute conditions. Tab is pinched and broken.
Pump is squeezed to deliver prefilled drug to the nozzle and nasal cavity
[277].
Bespak developed Unidose-DP™ resembling Flit Lizer technology.
This device comprises sealed container capable of delivering single shot
of drug. Unidose device has consistency between doses. Among 95% of
the dose delivered to the nasal passage, 60–70% reached to nasal ves-
tibular region limited use of this device for IN brain targeted delivery
[278]. Upon actuation compressed air in the container forced the pin to
rupture the membrane and drug is released. Antibody IgG has been
delivered via Unidose device and guided through MRI imaging tech-
nique.
SoluVent™- is powder based delivery device comprises a plunger
that exerts pressure on membrane and forces the powdered drug to
come out of device into nasal cavity. Vaccines have been delivered
through this device [279]. Monopowde device designed by the Aptar
group worked on the same mechanism of SoluVent™. When plunger is
pushed, positive pressure is created that ruptured the membrane and
drug is emitted. Animal studies using this device were conducted but
clinical studies on human are not available.
5.2. Liquid based devices
Liquid formulations are widely used for nasal delivery. Liquid based
devices mostly contain liquid solution, suspension or emulsion for-
mulations of drug. Nasal drops, sprays and metered dose nebulizer
deliver drug solutions. Liquid formulations act as humectants and
prevent dryness of mucosa in pathological conditions. Liquid formula-
tions are unstable due to microbial growth and chronic use requires
preservatives. Preservatives may cause mucosal irritation and allergy.
Liquid formulations have drawbacks of less stability of drug dissolved
in formulation and mucociliary action easily washed them away from
nasal mucosa. Construction of delivery device, physiochemical prop-
erties of drug and administration mode decide about the site of drug
deposition in nasal cavity and pattern of deposition.
5.2.1. Instillation and rhinyle catheter
Catheter delivers drugs to specific region of the nasal cavity. The
simplest way of drug delivery to nasal cavity is to insert catheter or
squirt tube in nostril and deliver liquid in defined site under visual
supervision. This technique is commonly used to anesthetize or sedate
the animals. Human mucosa is sensitive to mechanical injury and de-
position site and inconsistency in dosing are major concerning issues.
One side of the tube is inserted in the nostril and air is blown in the
other end through mouth to expel solution filled in the tube to the
nostril [280]. Although this technique is valid only for experimental
purposes but desmopressin rhinyle catheters are available in some
countries for treatment of diabetes inspidus, nocturnal enuresis and Von
Willebrand disease.
5.2.2. Drops
Drops are being used from decades for nasal drug delivery of liquid
formulations. They are cost effective and have easy manufacturing
process. Drops have risk of microbial contamination and chemical in-
stability. Mode of administration is important factor to decide fate of
formulations in nasal cavity. Previously, glass dropper with elongated
neck was used to administer liquid drop formations. Dropper filled with
liquid is inserted in nostril and rubber top is pressed to release the drug
in nostril. Dropper is feasible for single dose administration and me-
tered-dose spray pumps have taken their place for multidose adminis-
tration. Spray pumps are expensive and replaced by economical dis-
posable pipette for some clinical conditions. Pipettes are manufactured
through “blow-fill-seal” methodology and commonly used for nasal
decongestion and irrigation purposes. Fluticasone nasal delivery based
382
Journal of Controlled Release 268 (2017) 364–389
on spray pump is ineffective for treatment of nasal polyps. Nasal drops
formulations of fluticasone administered through pipette had got place
in European market. Nasal drop should deposit drug to the middle meat
us, region where polyps emerge [281]. Nasal drops delivered through
pipette have uncontrollable volume of administration and risk of con-
tamination. Head is downed during drops administration and large
volume is rapidly cleared to the laryngopharynx [282]. Drops have
limitations of discomfort, unacceptable to the patient and cause head-
ache.
5.2.3. Squeeze bottle
Importance of squeeze bottles is in local nasal drug delivery of to-
pical decongestants. It consists of partly air filled plastic bottles with
nozzle and jet outlet. On pressing the smooth bottle specific volume is
emitted through nozzle and delivered to the nasal cavity. On releasing
the pressure, air is filled again in the bottle. Squeeze bottle are not
efficient in delivering drugs to the deep region of the nasal cavity, hence
not effective for systemic or brain targeted delivery. This device is not
safe as delivery process contaminates the remaining volume with mi-
croorganisms and nasal secretions [283]. Administration of calculated
volume and deposition at particular site is difficult to control with this
delivery device. Force applied to press the device decides about the
dose and droplet size.
5.2.4. Metered-dose spray pumps and pressurized MDIs
Mostly nasal products in the market deliver liquid formulations
through metered-dose spray pumps. This system made easy delivery of
doses with consistency and reproducibility. Spray pumps usually used
for local delivery of nasal decongestants, antihistamines and corticos-
teroids or systemic administration of some drugs. Spray pump consists
of container, actuator and pump with valve. Operation of this system is
based on generation of fine mist by the hand operated pump and in-
stillation into the nasal cavity. Design of spray device, viscosity, droplet
size and plume geometry influence the deposition [283]. Targeting of
drugs to the nasal vestibule and nasal valve region is specialty of con-
ventional spray devices. However, only small volume is delivered with
metered-dose spray pump system and 2.5% of the administered volume
reaches olfactory region, made them unsuitable for nose to brain tar-
geting. Traditional spray pumps replace emitted liquid with air lead to
contaminations. Alteration in spray system design with the help of
novel technology negated preservative requirements and prevented
contamination associated with old spray pumps. Novel system com-
prises of collapsible bag, a movable piston, or a compressed gas to re-
place emitted liquid. Preservative free system is alternative to above
piston pump and involve filtration of air that replaces emitted liquid
through aseptic filter. This system is costly and complex and now a day
human friendly preservatives minimized the need of preservative free
system [284]. Recently spray pumps are modified with side actuation
and shorter tip to avoid mucosal damage. Fluticasone furoate has been
delivered with this novel system for seasonal rhinitis [280]. Modifica-
tion in pump system negated the need for priming, provided dose
counter and lock-out mechanisms for controlled and safe delivery.
Metered dose spray pumps have disadvantage of priming and not
control over dosing. They are used for administration of wide ther-
apeutic range drugs and not suitable for potent drugs. Single-dose or
duo-dose spray devices are reliable alternative to them. They deliver
single dose of costly drugs with accurate dosing. These devices com-
prise of vial, piston and swirl chamber. Actuator is pressed with thumb
while holding device in second and third fingers. Liquid is passed
through chamber with pressure and spray is formed. Currently mar-
keted products for migraine therapy are Imitrex and Zomig and FluMist
is the marketed influenza vaccine [285]. The filling process is sterilized,
emitted the need of preservatives but overfill is required like metered-
dose spray pump.
pMDIs are famous in nasal market for chronic respiratory disorders
such as asthma, COPD and bronchitis. Micronized particles are
A.R. Khan et al.
suspended in liquid propellants and aerosol droplets are produced upon
actuation. Commonly used chlorofluorocarbon (CFC) propellants de-
pleted the ozone layer and limited the potential of pMDI in the chronic
respiratory disorders and were withdrawn from market [286]. Now CFC
free propellants such as hydrofluoroalkane 134a have replaced CFC and
saved therapeutic advantages of pMDIs. pMDIs deliver bronchodilator,
corticosteroid and cromoglicate or nedocromil as mast cell stabilizers.
pMDIs provide aerosol droplets with small size, accurate, consistent and
calculated dose. pMDI comprises of plastic case with mouth piece, cap
for mouthpiece protection and pressurized metal canister containing
drug and propellants. Canister is pressed, upon actuation fine mist of
measured dose of a drug is passed though valve. Propellants are eva-
porated and fine particles are inhaled [287]. Propellants cause irritation
in the nasal cavity and dryness of mucus membrane. Upon actuation
pressurized aerosol droplets strike the mucus layer from short distance
with pressure and cause irritation. This phenomenon is called 'cold
Freon effect'. pMDIs deposit drug into anterior part of the nasal cavity
and not able to target upper posterior region beyond the nasal valve.
5.2.5. Pressurized olfactory device (POD)
The olfactory epithelium located between nose and brain accounts
for only 3–10% of the surface area of the nasal cavity in human. Its
location in the upper part of the nose with turbinate restriction made
consistent delivery of therapeutic molecules to this region challenging
[288,289]. POD has the ability to deposit a majority of drug at olfactory
region. These devices contain suitable tank, compressed air or nitrogen,
chlorofluorocarbon (CFC) or hydrofluoroalkane (HFA) as propellant
and air chamber as shown in Fig. 8. The air chamber is in connection
with the device via an internal compartment. Air chamber discharged
an aerosol spray into the nasal cavity through an applicator with an
orifice. When patient took the dose, the pneumatic solenoid is activated
and the compressed air is distributed through tubing to the air chamber
and then from chamber into the gas inlet of the housing. Pressurized gas
is rotated inside the spin chamber with circumferential helical velocity
or vortex-like velocity [290]. When the solenoid is triggered, the
elongated needle is displaced from the orifice to allow the fluid within
the fluid reservoir to escape. Pressurized gas passed through the orifice
created partial vacuum to force the fluid out of the reservoir through
the orifice [290].
POD device of the Impel NeuroPharma (Seattle, Washington) had
the ability to target the drug on the olfactory part of the nasal cavity.
Hoekman and Ho, developed the POD and compared with nasal drops
(to target respiratory region) and intraperitoneal injection (IP) to
Fig. 8. Pressurized Olfactory Device with its functional parts.
Modified from [290].
383
Journal of Controlled Release 268 (2017) 364–389
deliver morphine to rat. Experimental results showed that POD deliv-
ered drug to brain via olfactory pathway and pain was relieved. No
direct drug distribution to CNS was reported by IP injection through
systemic circulation and nasal drop through respiratory region. In ad-
dition to direct drug delivery to brain, POD also resulted in systemic
absorption of drug but not more than IP and nasal drop [290]. POD
technology is particularly exciting with molecules such as small pep-
tides and biologic agents, which are so rapidly destroyed in the blood
and are ineffective if given orally or intravenously. Interfering peptide
disrupted the interaction between the D1 and D2 dopamine receptors
for treating Major depressive disorder (MDD) and could be delivered to
relevant brain areas using the POD. Impel NeuroPharma IN POD de-
livered interfering peptide was studied for disruption of interaction
between D1 and D2 receptors. It was reported that interfering peptide
showed antidepressant-like effect up to 2 h after IN administration of
POD. Strong antidepressant-like effect induced by Interfering peptide
was comparable to that of imipramine, as confirmed by forced swim-
ming test (FST). It was also observed that interfering peptide disrupted
the D1–D2 interaction and were detected in the prefrontal cortex [291].
Nasal drops are conventional DDSs for delivery to nasal epithelium.
POD device was compared with nasal drop for nose to brain access.
POD device was constructed and investigated to deposit mannitol and
nelfinavir at olfactory epithelium for brain targeting. Compared to
nasal drops, POD administered mannitol and nelfinavir olfactory de-
position with POD in rats had shown 3.6-fold and 13.6-fold higher
cortex-to-blood ratio, respectively. It was concluded that deposition of
drug at olfactory region of nasal cavity by the POD resulted in higher
drug distribution to brain [292]. POD could be beneficial for transport
of both liquid and powder formulations through nasal epithelium.
Impel NeuroPharma utilized POD to deliver aqueous and powder form
of cholinergic reactivator (pralidoxime, 2-PAM) to CNS. POD delivered
significantly higher concentration of 2-PAM in brain and lower con-
centration in plasma than IV administration. Moreover, powder form
showed higher brain concentration than aqueous formulation. POD
deposited the formulations at olfactory epithelium and promoted direct
transport to brain [293].
5.2.6. Nebulizers and atomizers
Nebulizers are intended to enable the drug depositition to the upper
part of the nose, housing the neural connection between nose and brain.
Nebulizers break up liquid solution or suspension into small aerosol
droplets with the help of compressed gas or ultrasonic power.
Compared to tradational spray pumps, droplets produced from nebu-
lizer, upon nasal inhalation deposited to the upper posterior region of
the nasal cavity, thus promoted nose to brain targetting [294,295].
Chen et al. explored a novel, hands free nebulizer device for brain
tumor targetted delivery. Initial phase I/II clinical trial was conducted
on 37 patients of recurrent glioblastoma. Effect of perillyl alcohol
(POH) delivered intranasally via nebulizer on recurrent glioblastoma
was studied. They used light weight, portable, patients operated and
rechargable battery powered device. This study had shown positive
clinical effects and improved patient compliance up to 95% [296].
Further work reported that long-term IN POH chemotherapy was a safer
and effective approach for patients with recurrent glioblastoma. Kurve
Technology Inc., (Lynnwood, WA, USA) introduced ViaNase, a pocket-
sized advanced electronic atomizer incorporated Controlled Particle
Dispersion Technology. This technology has the ability to deliver wide
variety of solutions and suspensions with varying surface tension and
viscosity. ViaNase targeted the upper part of nose and sinus and thus its
potential could be utilized for nose to brain drug delivery [297,298]. IN
insulin was administered by ViaNase V atomizer for treatment of Alz-
heimer's disease and positive outcomes were reported [299]. Reduction
in pulmonary function was concerning issue, limited the benefits of this
technology [300]. Wolfe Tory Medical designed "MAD Nasal™ IN Mu-
cosal Atomization Device". They utilized this novel atomizer to in-
tranasally deliver neuroprotective agents during cryonics to prevent
A.R. Khan et al.
ischemic damage to brain. IN Atomization Device delivery was an al-
ternative to intravenous or intraosseous delivery [301]. Recently, vi-
brating mesh and jet nebulizers have gained attention to test the ol-
factory deposition of aerosol medicines. A study was conducted to
examine the olfactory delivery via vibrating mesh and jet nebulizers in
a nasal model. Normal and bidirectional delivery concept and Sar Gel
technique to visualize particle deposition was applied. Mesh nebulizer
using bidirectional technique, significantly, enhanced deposition in
olfactory region than PARI Sinus nebulizer. Higher speed aerosols
generated from PARI Sinus nebulizer penetrated deeper into dorsal
passage. Bidirectional delivery was superior in depositing aerosol into
nasal cavity and olfactory region than normal delivery. It was con-
cluded that mesh-typed nebulizer with bidirectional concept was better
choice for olfactory targeting [302]. In another study, protein aerosol
for IN delivery to brain was investigated using vibrating mesh nebu-
lizer. Diffusion of different molecular weight sized protein, concentra-
tions and formulations across human nasal epithelial cells model was
studied. Diffusion of FAB was significantly higher than that of IgG A.
Higher concentration of IgG showed more diffusion than lower con-
centration. Mesh nebulizer improved the stability of proteins and in-
creased deposition across nose model. This system was suitable for nose
to brain delivery of protein aerosol [303].
5.3. Patents on nasal drug delivery devices
Many patent applications on IN administration for CNS drug de-
livery have been filed and granted in the past 10 years. A patent was
awarded to Impel Neuropharma Inc., with title of “Nasal drug delivery
device” for nose to brain delivery of drug [127]. Similarly, US patent
[304] and Chinese patent [305] have also been awarded for same in-
vention. World Intellectual Property Organization (WIPO) published a
patent of Tongli Biomedical titled “Brain-Targeted Nasal Drug Delivery
Device and Body Position Fixator Thereof”. Chinese inventors applied a
specially designed body position fixator to keep the body position of a
user in such a position so that nasally delivered drug could reach to
olfactory region. Fixator kept the user in the above-mentioned body
position and drug is delivered to target the brain by an applicator
having a shape matching the nasal cavity of user. With the help of
fixator and smart controlling element, an applicator delivered drug is
targeted to olfactory region of nasal cavity at required time for direct
nose to brain targeting [306].
6. Conclusion
In summary, an analysis of the available literatures has revealed
that brain targeting via nasal drug delivery is an attractive approach.
Surface modifications of nanocarriers and the introduction of specific
ligands provided useful information and progress in this field. Surface
modifications of carriers with CPP (NPs, micelles and liposomes)
opened a new era of drug delivery systems especially peptides and
protein based therapeutic agents to brain. Most research publications
focused on prevention and management of neurological disorders but
intranasally administered TAT modified micelles and chitosan NPs have
shown potential for targeting different types of brain tumors hence,
more efforts are required to explore brain tumor targeted novel IN
DDSs. Nasal drug delivery systems also have some limitations such as
small quantities of drugs could be administered with increasing drug
molecular weight [3]. The partial degradation of some molecules in
nasal cavity and nasal mucosa toxicity was also a drawback of this
route. Nasal drug delivery devices could overcome these problems re-
lated with DDSs, in near future, more complex and automatic operating
delivery devices for chronic dosing and treatment of brain tumors
would be demanded. Available delivery devices deposited drug at re-
spiratory epithelium alongwith deep part of the nasal cavity, leading to
the systemic absorption. Novel drug delivery devices are under devel-
opment to overcome barriers related to complex geometry of the nasal
384
Journal of Controlled Release 268 (2017) 364–389
cavity and strictly deposit drug only at olfactory region without sys-
temic exposure. Clinical and preclinical trials of nasal DDSs and devices
should be conducted to ensure specificity for brain tissues using novel
targeting moieties. Thus, to further explore potential of novel IN DDSs
and devices for an efficient and effective delivery of potential drugs to
brain more efforts are required. Recently, many drugs have been suc-
cessfully delivered to brain via nasal administration and products based
on novel nasal nanoformulations for brain targeting will be available in
market. This route is predicted to be utilized not only for therapeutic
but also diagnostic purposes [307].
Acknowledgements
This work was supported by the China-Australia Centre for Health
Sciences Research (CACHSR no. 2016GJ01).
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.jconrel.2017.09.001.
References
[1] BrainFacts.org, The Blood Brain Barrier. http://www.brainfacts.org/brainbasics/
neuroanatomy/articles/2014/blood-brain-barrier.
[2] W.M. Pardridge, The blood-brain barrier: bottleneck in brain drug development,
NeuroRx 2 (2005) 3–14.
[3] A. Mistry, S. Stolnik, L. Illum, Nanoparticles for direct nose-to-brain delivery of
drugs, Int. J. Pharm. 379 (2009) 146–157.
[4] L. Illum, Transport of drug from nasal cavity to the central nervous system, Eur. J.
Pharm. Sci. 11 (2000) 1–18.
[5] M.V. Woensel, N. Wauthoz, R. Rosiere, K. Amighi, V. Mathieu, F. Lefranc,
S.W. Gool, S.D. Valeeschouwer, Formulation for intranasal delivery of pharma-
cological agents to combat brain disease: a new opportunity to tackle GBM?
Cancer 5 (2013) 1020–1048.
[6] S.I. Rapoport, P.J. Robinson, Tight-junctional modification as the basis of osmotic
opening of the blood-brain barrier, Ann. N. Y. Acad. Sci. 481 (1986) 250–267.
[7] S. Joshi, A. Ergin, M. Wang, R.R. Reif, J. Zhang, J.N. Bruce, I.J. Bigio, Inconsistent
blood brain barrier disruption by intraarterial mannitol in rabbits: implications for
chemotherapy, J. Neuro-Oncol. 104 (2011) 11–19.
[8] A. Rodriguez, S.B. Tatter, W. Debinski, Neurosurgical techniques for disruption of
the blood-brain barrier for glioblastoma treatment, Pharmaceutics 7 (2015)
175–187.
[9] E.A. Neuwelt, P.A. Barnett, C.I. McCormick, L.G. Remsen, R.A. Kroll, G. Sexton,
Differential permeability of a human brain tumor xenograft in the nude rat: impact
of tumor size and method of administration on optimizing delivery of biologically
diverse agents, Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 4 (1998)
1549–1555.
[10] A. Gregor, M. Lind, H. Newman, C. Osborn, Phase II studies of RMP-7 and car-
boplatin in the treatment of recurrent high grade glioma. RMP-7 European Study
Group, J. Neuro-Oncol. 44 (1999) 137–145.
[11] M.D. Prados, S.J.S. Schold, H.A. Fine, K. Jaeckle, F. Hochberg, L. Mechtler,
M.R. Fetell, S. Phuphanich, L. Feun, T.J. Janus, K. Ford, W. Graney, A randomized,
double-blind, placebo controlled, phase 2 study of RMP-7 in combination with
carboplatin administered intravenously for the treatment of recurrent malignant
glioma, Neuro-Onco 5 (2003) 96–103.
[12] A.I. Qureshi, M. Fareed, K. Suri, J. Khan, M. Sharma, K. Olson, L.R. Guterman,
L.N. Hopkins, Superselective intra-arterial carboplatin for treatment of in-
tracranial neoplasms: experience in 100 procedures, J, Neuro-Oncology 51 (2001)
151–158.
[13] L.B. Liu, Y.X. Xue, Y.H. Liu, Bradykinin increases the permeability of the blood-
tumor barrier by the caveolae-mediated transcellular pathway, J. Neuro-Oncol. 99
(2010) 187–194.
[14] H. Zhang, Y.T. Gu, Y.X. Xue, Bradykinin-induced blood-brain tumor barrier per-
meability increase is mediated by adenosine 5′-triphosphate-sensitive potassium
channel, Brain Res. 1144 (2007) 33–41.
[15] K. Matsukado, T. Inamura, S. Nakano, M. Fukui, R.T. Bartus, K.L. Black, Enhanced
tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid
infusion of bradykinin analog, RMP-7, Neurosurgery 39 (1996) 125–134.
[16] C.V. Borlongan, D.F. Emerich, Facilitation of drug entry into the CNS via transient
permeation of blood brain barrier: laboratory and preliminary clinical evidence
from Bradykinin receptor agonist, Cereport, Brain Res. Bull. 60 (2003) 297–306.
[17] E. Sanovich, R.T. Bartus, P.M. Friden, R.L. Dean, H.Q. Le, M.W. Brightman,
Pathway across bloodbrain barrier opened by the bradykinin agonist, RMP-7,
Brain Res. 705 (1995) 125–135.
[18] M.D. Prados, S.J.S. Schold, H.A. Fine, K. Jaeckle, F. Hochberg, L. Mechtler,
M.R. Fetell, S. Phuphanich, L. Feun, T.J. Janus, K. Ford, W. Graney, A randomized,
double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with
carboplatin administered intravenously for the treatment of recurrent malignant
glioma, Neuro-Oncology 5 (2003) 96–103.
[19] Y.C. Kuo, C.L. Lee, Methylmethacrylate-sulfopropylmethacrylate nanoparticles
with surface RMP-7 for targeting delivery of antiretroviral drugs across the blood-
A.R. Khan et al.
brain barrier, Colloids Surf. B: Biointerfaces 90 (2012) 75–82.
[20] N.G. Rainov, K. Ikeda, N.H. Qureshi, S. Grover, U. Herrlinger, P. Pechan,
E.A. Chiocca, X.O. Breakefield, F.H. Barnett, Intraarterial delivery of adenovirus
vectors and liposome-DNA complexes to experimental brain neoplasms, Hum.
Gene Ther. 10 (1999) 311–318.
[21] N. Das, B. Raay, M.K. Basu, Effect of angiotensin II on liposome uptake by the rat
brain in vivo, Indian J. Exp. Biol. 37 (1999) 871–875.
[22] E.J. Park, Y.Z. Zhang, N. Vykhodtseva, N. McDannold, Ultrasound-mediated
blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab
in a breast cancer brain metastasis model, J. Control. Release 163 (2012) 277–284.
[23] C. Horodyckid, M. Canney, A. Vignot, R. Boisgard, A. Drier, G. Huberfeld,
C. François, A. Prigent, M.D. Santin, C. Adam, J.C. Willer, C. Lafon, J.Y. Chapelon,
A. Carpentier, Safe long-term repeated disruption of the blood-brain barrier using
an implantable ultrasound device : a multiparametric study in primates, J.
Neurosurg. (2015).
[24] K. Hynynen, N. McDannold, N.A. Sheikov, F.A. Jolesz, N. Vykhodtseva, Local and
reversible blood-brain barrier disruption by noninvasive focused ultrasound at
frequencies suitable for trans-skull sonications, Neuro Image 24 (2005) 12–20.
[25] M.A. O'Reilly, Y. Huang, K. Hynynen, The impact of standing wave effects on
transcranial focused ultrasound disruption of the blood-brain barrier in a rat
model, Phys. Med. Biol. 55 (2010) 5251–5267.
[26] M. Aryal, C.D. Arvanitis, P.M. Alexander, N. McDannold, Ultrasound-mediated
blood-brain barrier disruption for targeted drug delivery in the central nervous
system, Adv. Drug Deliv. Rev. 0 (2014) 94–109.
[27] T.D. Azad, J. Pan, I.D. Connolly, A. Remington, C.M. Wilson, G.A. Grant,
Therapeutic strategies to improve drug delivery across the blood-brain barrier,
Neurosurg. Focus. 38 (2015) E9.
[28] K.C. Wei, P.C. Chu, H.Y. Wang, C.Y. Huang, P.Y. Chen, H.C. Tsai, Y.J. Lu, P.Y. Lee,
I.C. Tseng, L.Y. Feng, P.W. Hsu, T.C. Yen, H.L. Liu, Focused ultrasound-induced
blood-brain barrier opening to enhance temozolomide delivery for glioblastoma
treatment: a preclinical study, PLoS One 8 (2013) e58995.
[29] J. Mei, Y. Cheng, Y. Song, Y. Yang, F. Wang, Y. Liu, Z. Wang, Experimental study
on targeted methotrexate delivery to the rabbit brain via magnetic resonance
imaging-guided focused ultrasound, J. Ultrasound Med. 28 (2009) 871–880.
[30] A. Burgess, Y. Huang, W. Querbes, D.W. Sah, K. Hynynen, Focused ultrasound for
targeted delivery of siRNA and efficient knockdown of Htt expression, J. Control.
Release 163 (2012) 125–129.
[31] R. Alkins, A. Burgess, M. Ganguly, G. Francia, R. Kerbel, W.S. Wels, K. Hynynen,
Focused ultrasound delivers targeted immune cells to metastatic brain tumors,
Cancer Res. 73 (2013) 1892–1899.
[32] E. Nance, K. Timbie, G.W. Miller, J. Song, C. Louttit, A.L. Klibanov, T.Y. Shih,
G. Swaminathan, R.J. Tamargo, G.F. Woodworth, J. Hanes, R.J. Price, Non-in-
vasive delivery of stealth, brain-enetrating nanoparticles across the blood-brain
barrier using MRI-guided focused ultrasound, J. Control. Release 189 (2014)
123–132.
[33] M. Aryal, N. Vykhodtseva, Y.Z. Zhang, J. Park, N. McDannold, Multiple treatments
with liposomal doxorubicin and ultrasound-induced disruption of blood-tumor
and blood-brain barriers improve outcomes in a rat glioma model, J. Control.
Release 169 (2013) 103–111.
[34] R.J. Diaz, P.Z. McVeigh, M.A. O'Reilly, K. Burrell, M. Bebenek, C. Smith, A. Etame,
G. Zadeh, K. Hynynen, B.C. Wilson, J.T. Rutka, Focused ultrasound delivery of
Raman nanoparticles across the blood brain barrier: potential for targeting ex-
perimental brain tumors, Nanomedicine 10 (2014) 1075–1087.
[35] R. Price, Ultrasound-targeted nanoparticle delivery across the blood-brain barrier,
J Ther. Ultrasound 3 (2015) O20.
[36] W.J. Fry, W.H. Mosberg Jr., J.W. Barnard, F.J. Fry, Production of focal destructive
lesions in the central nervous system with ultrasound, J. Neurosurg. 11 (1954)
471–478.
[37] A. Chapman, G. ter Haar, Thermal ablation of uterine fibroids using MR-guided
focused ultrasound-a truly non-invasive treatment modality, Eur. Radiol. 17
(2007) 2505–2511.
[38] R. Catane, A. Beck, Y. Inbar, T. Rabin, N. Shabshin, S. Hengst, R.M. Pfeffer,
A. Hanannel, O. Dogadkin, B. Liberman, D. Kopelman, MR-guided focused ultra-
sound surgery (MRgFUS) for the palliation of pain in patients with bone metas-
tases–preliminary clinical experience, Ann. Oncol. 18 (2007) 163–167.
[39] D.J. Begley, L.K. Squires, B.V. Zlokovic, D.M. Mitrovic, C.C.W. Hughes,
P.A. Revest, J. Greenwood, J. Neurochem. 55 (1998) 1222–1230.
[40] U. Jaehde, M.W.E. Langemeije, A.G. de Boer, D.D. Breimer, Cerebrospinal fluid
transport and disposition of the quinolones ciprofloxacin and pefloxacin in rats, J.
Pharmacol. Exp. Ther. 263 (1992) 1140–1146.
[41] D.R. Groothuis, H. Benalcazar, C.V. Allen, R.M. Wise, C. Dills, C. Dobrescu,
V. Rothholtz, R.M. Levy, Comparison of cytosine arabinoside delivery to rat brain
by i.v, intrathecal, intraventricular and intraparenchymal routes of administra-
tion, Brain Res. 856 (2000) 281–290.
[42] J.A. MacKay, D.F. Deen, F.C. Szoka, Distribution in brain liposomes after con-
vection enhanced delivery; modulation by particle charge, particle diameter and
presence of steric coating, Brain Res. 1035 (2005) 129–135.
[43] M.J. Mahoney, W.M. Saltman, Controlled release of proteins to tissue transplants
for treatments of neurodegenerative disorders, J. Pharm. Sci. 85 (1996)
1276–1281.
[44] C. Nicholson, E. Sykova, Extracellular space structure revealed by diffusion ana-
lysis, Trends Neuro. Sci. 21 (1998) 207–215.
[45] O. Lewis, M. Woolley, D. Johnson, A. Rosser, N.U. Barua, A.S. Bienemann,
S.S. Gill, S. Evans, Chronic, intermittent convection-enhanced delivery devices, J.
Neurosci. Methods 259 (2016) 47–56.
[46] M.A. Vogelbaum, M.K. Aghi, Convection-enhanced delivery for the treatment of
glioblastoma, Neuro-Oncology 17 (2015) ii3–ii8.
[47] M.F. Lam, M.G. Thomas, C.R. Lind, Neurosurgical convection-enhanced delivery of
treatments for Parkinson's disease, J. Clin. Neurosci. 18 (2011) 1163–1167.
[48] M.M. Nordling-David, R. Yaffe, D. Guez, H. Meirow, D. Last, E. Grad, S. Salomon,
S. Sharabi, Y. Levi-Kalisman, G. Golomb, Y. Mardo, Liposomal temozolomide drug
385
Journal of Controlled Release 268 (2017) 364–389
delivery using convection enhanced delivery, J. Control. Release 261 (2017)
138–146.
[49] M.S. Fiandaca, J.R. Forsayeth, P.J. Forsayeth, K.S. Bankiewicz, Image-guided
convection-enhanced delivery platform in the treatment of neurological diseases,
Neurotherapeutics 5 (2008) 123–127.
[50] J.K. Saucier-Sawyer, Y.E. Seo, A. Gaudin, E. Quijano, E. Song, A.J. Sawyer,
Y. Deng, A. Huttner, W.M. Saltzman, Distribution of polymer nanoparticles by
convection-enhanced delivery to brain tumors, J. Control. Release 23 (2016)
103–112.
[51] H. Brem, M.S. Mahaley Jr., N.A. Vick, K.L. Black, S.C. Schold Jr., P.C. Burger,
A.H. Friedman, I.S. Ciric, T.W. Eller, J.W. Cozzens, Interstitial chemotherapy with
drug polymer implants for the treatment of recurrent gliomas, J. Neurosurg. 74
(1991) 441–446.
[52] G.L. Gallia, S. Brem, H. Brem, Local treatment of malignant brain tumors using
implantable chemotherapeutic polymers, J. Natl. Compr. Cancer Netw. 3 (2005)
721–728.
[53] P.P. Wang, J. Frazier, H. Brem, Local drug delivery to the brain, Adv. Drug Deliv.
Rev. 54 (2002) 987–1013.
[54] R.V. La Rocca, M.H. Maximilian, Localized BCNU chemotherapy and the multi-
modal management of malignant glioma, Curr. Med. Res. Opin. 25 (2009)
149–160.
[55] K. Kawano, M. Watanabe, T. Yamamoto, M. Yokoyama, P. Opanasopit, T. Okano,
Y. Maitani, Enhanced antitumor effect of camptothecin loaded in long-circulating
polymeric micelles, J. Control. Release 112 (2006) 329–332.
[56] M. Staples, Microchips and controlled-release drug reservoirs, WIREs Nanomed.
Nanobiotech. 2 (2010) 400–417.
[57] K.B. Sutradhar, C.D. Sumi, Implantable microchip: the futuristic controlled drug
delivery system, Drug Deliv. 23 (2016).
[58] B.C. Masi, B.M. Tyler, H. Bow, R.T. Wicks, Y. Xue, H. Brem, R. Langer, M.J. Cima,
Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model,
Biomaterials 33 (2012) 5768–5775.
[59] G.Y. Kim, M.J. Chima, M.M. Tupper, J.M. Karp, R.S. Langer, H. Brem, M. Cima,
Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L
flank model, J. Control. Release 123 (2007) 172–178.
[60] A.G. De Boer, P.J. Gaillard, Drug targeting to the brain, Annu. Rev. Pharmacol.
Toxicol. 47 (2007) 323–355.
[61] M. Minocha, V. Khurana, B. Qin, D. Pal, A.K. Mitra, Enhanced brain accumulation
of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or
erlotinib, Int. J. Pharm. 436 (2012) 127–134.
[62] R. Callaghan, F. Luk, M. Bebawy, Inhibition of the multidrug resistance P-glyco-
protein: time for a change of strategy? Drug Metab. Dispos. 42 (2014) 623–631.
[63] P. Breedveld, J.H. Beijnen, J.H. Schellens, Use of P-glycoprotein and BCRP in-
hibitors to improve oral bioavailability and CNS penetration of anticancer drugs,
Trends Pharmacol. Sci. 27 (2006) 17–24.
[64] X.R. Song, Z. Cai, Y. Zheng, G. He, F.Y. Cui, D.Q. Gong, S.X. Hou, S.J. Xiong,
X.J. Lei, Y.Q. Wei, Reversion of multidrug resistance by co-encapsulation of vin-
cristine and verapamil in PLGA nanoparticles, Eur. J. Pharm. Sci. 37 (2009)
300–305.
[65] Y. Patil, T. Sadhukha, L. Ma, J. Panyam, Nanoparticle-mediated simultaneous and
targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance, J.
Control. Release 136 (2009) 21–29.
[66] N.R. Patel, A. Rathi, D. Mongayt, V.P. Torchilin, Reversal of multidrug resistance
by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating lipo-
somes, Int. J. Pharm. 416 (2011) 296–299.
[67] C. Sarisozen, I. Vural, T. Levchenko, A.A. Hincal, V.P. Torchilin, Long-circulating
PEG-PE micelles coloaded with paclitaxel and elacridar (GG918) overcome mul-
tidrug resistance, Drug Deliv. 19 (2012) 363–370.
[68] S. Shukla, S. Ohnuma, S.V. Ambudkar, Improving cancer chemotherapy with
modulators of ABC drug transporters, Curr. Drug Targets 12 (2011) 621–630.
[69] B. Pavan, A. Dalpiaz, Prodrugs and endogenous transporters: are they suitable
tools for drug targeting into the central nervous system? Curr. Pharm. Des. 17
(2011) 3560–3576.
[70] R.K. Singh, D.N. Prasad, T.R. Bhardwaj, Design, synthesis, chemical and biological
evaluation of brain targeted alkylating agent using reversible redox prodrug ap-
proach, Arab. J. Chem. 10 (2017) 420–429.
[71] P. Chen, N. Bodor, W.M. Wu, L. Prokai, Strategies to target kyotorphin analogues
to the brain, J. Med. Chem. 41 (1998) 3773–3781.
[72] M. Gynther, K. Laine, J. Ropponen, J. Leppänen, A. Mannila, T. Nevalainen,
J. Savolainen, T. Järvinen, J. Rautio, Large neutral amino acid transporter enables
brain drug delivery via prodrugs, J. Med. Chem. 51 (2008) 932–936.
[73] M. Mavroudi, P. Zarogoulidis, K. Porpodis, I. Kioumis, S. Lampaki, L. Yarmus,
R. Malecki, K. Zarogoulidis, M. Malecki, Stem cells' guided gene therapy of cancer:
new frontier in personalized and targeted therapy, J. Cancer Res. Ther. 2 (2014)
22–33.
[74] B. Engelhardt, R.M. Ransohoff, Capture, crawl, cross: the T cell code to breach the
bloodbrain barriers, Trends Immunol. 33 (2012) 579–589.
[75] N.S. Ivey, A.G. Maclean, A.A. Lackner, Acquired immunodeficiency syndrome and
the bloodbrain barrier, J. NeuroVirol. 15 (2009) 111–122.
[76] S.K. Baek, A.R. Makkouk, T. Krasieva, C.H. Sun, S.J. Madsen, H. Hirschberg,
Photothermal treatment of glioma; an in vitro study of macrophage-mediated
delivery of gold nanoshells, J. Neuro-Oncol. 104 (2011) 439–448.
[77] K.B. Johnsen, J.M. Gudbergsson, M.N. Skov, L. Pilgaard, T. Moos, M.A. Duroux,
Comprehensive overview of exosomes as drug delivery vehicles endogenous na-
nocarriers for targeted cancer therapy, Biochim. Biophys. Acta Rev. Cancer 1846
(2014) 75–87.
[78] N.D. Mazarakis, M. Azzouz, J.B. Rohll, F.M. Ellard, F.J. Wilkes, A.L. Olsen,
E.E. Carter, R.D. Barber, D.F. Baban, S.M. Kingsman, A.J. Kingsman, K. O'Malley,
K.A. Mitrophanous, Rabies virus glycoprotein pseudotyping of lentiviral vectors
enables retrograde axonal transport and access to the nervous system after per-
ipheral delivery, Hum. Mol. Genet. 10 (2001) 2109–2121.
[79] J.K. Liu, Q. Teng, M. Garrity-Moses, T. Federici, D. Tanase, M.J. Imperiale,
A.R. Khan et al.
N.M. Boulis, A novel peptide defined through phage display for therapeutic pro-
tein and vector neuronal targeting, Neurobiol. Dis. 19 (2005) 407–418.
[80] M.E. Hegi, P. Rajakannu, M. Weller, Epidermal growth factor receptor: a re-
emerging target in glioblastoma, Curr. Opin. Neurol. 25 (2012) 774–779.
[81] X. Hong, C. Miller, S. Savant-Bhonsale, S.N. Kalkanis, Antitumor treatment using
interleukin-12- secreting marrow stromal cells in an invasive glioma model,
Neurosurgery 64 (2009) 1139–1146 (discussion 1146-1137).
[82] K. Shah, Mesenchymal stem cells engineered for cancer therapy, Adv. Drug Deliv.
Rev. 64 (2012) 739–748.
[83] J. Kranzler, M.A. Tyler, A.M. Sonabend, I.V. Ulasov, M.S. Lesniak, Stem cells as
delivery vehicles for oncolytic adenoviral virotherapy, Curr. Gene. Ther. 9 (2009)
389–395.
[84] M. Duebgen, J. Martinez-Quintanilla, K. Tamura, S. Hingtgen, N. Redjal,
H. Wakimoto, K. Shah, Stem cells loaded with multimechanistic oncolytic herpes
simplex virus variants for brain tumor therapy, J. Natl. Cancer Inst. 106 (2014)
dju090.
[85] A. Béduneau, P. Saulnier, J.P. Benoit, Active targeting of brain tumors using na-
nocarriers, Biomaterials 28 (2007) 4947–4967.
[86] H.Y. Yoon, S. Son, S.J. Lee, D.G. You, J.Y. Yhee, J.H. Park, M. Swierczewska,
S. Lee, I.C. Kwon, S.H. Kim, K. Kim, M.G. Pomper, Glycol chitosan nanoparticles as
specialized cancer therapeutic vehicles: sequential delivery of doxorubicin and
Bcl-2 siRNA, Sci Rep 4 (2014) 6878.
[87] J. Bruun, T.B. Larsen, R.I. Jølck, R. Eliasen, R. Holm, T. Gjetting, T.L. Andresen,
Investigation of enzyme-sensitive lipid nanoparticles for delivery of siRNA to
blood-brain barrier and glioma cells, Int. J. Nanomedicine 10 (2015) 5995–6008.
[88] S. Martins, I. Tho, I. Reimold, E. Souto, D. Ferreira, M. Brandl, Brain delivery of
camptothecin by means of solid lipid nanoparticles: formulation design, in vitro
and in vivo studies, Int. J. Pharm. 439 (2012) 49–62.
[89] M. Zhao, J. Chang, X. Fu, C. Liang, S. Liang, R. Yan, A. Li, Nano-sized cationic
polymeric magnetic liposomes significantly improve drug delivery to the brain in
rats, J. Drug Target. 20 (2012) 416–421.
[90] P.J. Gaillard, C.C.M. Appeldoorn, R. Dorland, J.V. Kregten, F. Manca, D.J. Vugts,
B. Windhorst, G.A.M.S. van Dongen, H.E. de Vries, D. Maussang, O.V. Tellingen,
Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of
glutathione pegylated liposomal doxorubicin (2B3-101), PLoS One 9 (2014)
82331.
[91] J. Huwyler, D. Wu, W.I. Ardridge, Brain drug delivery of small molecules using
Immunoliposomes, PNAS 93 (1996) 14164–14169.
[92] R.J.L. Ippens, Liposomal daunorubicin (DaunoXome) in children with recurrent or
progressive brain tumors, Pediatr. Hematol. Oncol. 16 (1999) 131–139.
[93] S. Serres, M.S. Soto, A. Hamilton, M.A. McAteer, W.S. Carbonell, M.D. Robson,
O. Ansorge, A. Khrapitchev, C. Bristow, L. Balathasan, T. Weissensteiner,
Molecular MRI enables early and sensitive detection of brain metastases, PNAS
109 (2012) 6674–6679.
[94] F. Dilnawaz, A. Singh, S. Mewar, U. Sharma, N.R. Jagannathan, S.K. Sahoo, The
transport of non-surfactant based paclitaxel loaded magnetic nanoparticles across
the blood brain barrier in a rat model, Biomaterials 33 (2012) 2936–2951.
[95] S. Roy, Strategic drug delivery targeted to the brain: a review, Der Pharmac. Sin. 3
(2012) 76–92.
[96] R.T. Jackson, J. Tigges, W. Arnold, Arch. Otolaryngol. 105 (1979) 180–184.
[97] D. Sanjay, B. Mahantil, B. Majumder, Der Pharmac. Sin. 2 (2011) 94–106.
[98] P.O. Freskgård, J. Niewoehner, E. Urich, Time to open the blood–brain barrier gate
for biologics? Future Neurol. 9 (2015) 243–245.
[99] E.A. Neuwelt, B. Bauer, C. Fahlke, G. Fricker, C. Iadecola, D. Janigro, L. Leybaert,
Z. Molnár, M.E. O'Donnell, J.T. Povlishock, N.R. Saunders, F. Sharp,
D. Stanimirovic, R.J. Watts, L.R. Drewes, Engaging neuroscience to advance
translational research in brain barrier biology, Nat. Rev. Neurosci. 12 (2011)
169–182.
[100] Alz forum. AD monoclonals. http://www.alzforum.org/news/
conferencecoverage/aducanumab-solanezumab-gantenerumab-data-lift-
crenezumab-well August 10 (2015).
[101] R.S. Doody, M. Farlow, P.S. Aisen, Alzheimer's disease cooperative study data,
A. & publication, C. phase 3 trials of solanezumab and bapineuzumab for
Alzheimer's disease, N. Engl. J. Med. 370 (2014) 1460.
[102] P.O. Freskgård, E. Urich, Antibody therapies in CNS diseases, Neuropharmacology
120 (2016) 38–55.
[103] A. Chaudhuri, P.O. Behan, Natalizumab for relapsing multiple sclerosis, N. Engl. J.
Med. 348 (2003) 1598–1599.
[104] P.S. Sorensen, S. Lisby, R. Grove, F. Derosier, S. Shackelford, E. Havrdova,
J. Drulovic, M. Filippi, Safety and efficacy of ofatumumab in relapsing-remitting
multiple sclerosis: a phase 2 study, Neurology 82 (2014) 573–581.
[105] Roche, Roche's ocrelizumab significantly reduced both relapses and disability
progression versus interferon beta-1a (Rebif®) in two Phase III studies in multiple
sclerosis, http://www.roche.com/media/store/releases/med-cor-2015-06-30.
htm, (2015).
[106] Roche, Ocrelizumab first investigational medicine to show efficacy in people with
primary progressive multiple sclerosis in large Phase III study, http://www.roche.
com/investors/updates/inv-update-2015-09-28.htm, (2015).
[107] R.B. Pepinsky, Z. Shao, B. Ji, Q. Wang, G. Meng, L. Walus, X. Lee, Y. Hu, C. Graff,
E. Garber, W. Meier, S. Mi, Exposure levels of anti-LINGO-1 Li81 antibody in the
central nervous system and dose-efficacy relationships in rat spinal cord re-
myelination models after systemic administration, J. Pharmacol. Exp. Ther. 339
(2011) 519–529.
[108] S. Mi, B. Hu, K. Hahm, Y. Luo, E.S.K. Hui, Q. Yuan, W.M. Wong, L. Wang, H. Su,
T.H. Chu, J. Guo, W. Zhang, K.F. So, B. Pepinsky, Z. Shao, C. Graff, E. Garber,
V. Jung, E.X. Wu, W. Wu, LINGO-1 antagonist promotes spinal cord remyelination
and axonal integrity in MOG-induced experimental autoimmune en-
cephalomyelitis, Nat. Med. 13 (2007) 1228–1233.
[109] D. Wickramasinghe, Tumor and T cell engagement by BiTE, Discov. Med. 16
(2013) 149–152.
[110] Y.J. Yu, Y. Zhang, M. Kenrick, K. Hoyte, W. Luk, Y. Lu, J. Atwal, J.M. Elliott,
386
Journal of Controlled Release 268 (2017) 364–389
S. Prabhu, R.J. Watts, M.S. Dennis, Boosting brain uptake of a therapeutic anti-
body by reducing its affinity for a transcytosis target, Sci. Transl. Med. 3 (2011)
84ra44.
[111] L. Tengfei, M. Vandesquill, F. Koukouli, C. Dudeffant, I. Youssef, P. Lenormand,
C. Ganneau, U. Maskos, C. Czech, F. Grueninger, C. Duyckaerts, M. Dhenain,
S. Bay, B. Delatour, P. Lafaye, Camelid single-domain antibodies: a versatile tool
for in vivo imaging of extracellular and intracellular brain targets, J. Control.
Release 243 (2016) 1–10.
[112] S. Kyoungho, Lipocalin-2 as a therapeutic target for brain injury: an astrocentric
perspective, Prog. Neurobiol. 144 (2016) 158–172.
[113] E. Venereau, F.D. Leo, R. Mezzapelle, G. Careccia, G. Musco, M.E. Bianchi, HMGB1
as biomarker and drug target, Pharmacol. Res. 111 (2016) 534–544.
[114] A. Ben-Zvi, B. Lacoste, E. Kur, B.J. Andreone, Y. Mayshar, H. Yan, C. Gu, Mfsd2a is
critical for the formation and function of the blood–brain barrier, Nature 509
(2014) 507–511.
[115] L.N. Nguyen, D. Ma, G. Shui, P. Wong, A. Cazenave-Gassiot, X. Zhang, M.R. Wenk,
E.L. Goh, D.L. Silver, Mfsd2a is a transporter for the essential omega-3 fatty
aciddocosahexaenoic acid, Nature 509 (2014) 503–506.
[116] C. Gu, A. Ben-Zvi, Modulating or treating permeability of blood–brain barrierby
administering inhibitor of gene, or agonist of gene, or gene expressionproduct e.g.
major facilitator superfamily domain-containing protein 2(Mfsd2A) to human,
Harvard College (Hard-C), p. 131. Internationalapplication number: PCT/US2014/
043395, International publication number: WO 2014/205338 A2.
[117] C. Betsholtz, Lipid transport and human brain development, Nat. Genet. 47 (2015)
699–701.
[118] W.M. Pardridge, Blood–brain barrier endogenous transporters astherapeutic tar-
gets: a new model for small molecule CNS drug discovery, Expert Opin. Ther.
Targets 19 (2015) 1059–1072.
[119] L. Peura, K. Malmioja, K. Huttunen, J. Leppanen, M. Hamalainen, M.M. Forsberg,
J. Rautio, K. Laine, Design, synthesis and brain uptake of LAT1-targeted aminoacid
prodrugs of dopamine, Pharm. Res. 30 (2013) 2523–2537.
[120] A. Vyas, A. Jain, P. Hurkat, A. Jain, S.K. Jain, Targeting of AIDS re-
latedencephalopathy using phenylalanine anchored lipidic nanocarrier, Colloids
Surf. B: Biointerfaces 131 (2015) 155–161.
[121] X.C. Yu, J.J. Yang, B.H. Jin, H.L. Xu, H.Y. Zhang, J. Xiao, C.T. Lu, Y.Z. Zhao,
W. Yang, A strategy for bypassing the blood-brain barrier: facial intradermal
braintargeted delivery via the trigeminal nerve, J. Control. Release 258 (2017)
22–33.
[122] T. Fernandez, F. Pozo, Induction of cell death in a glioblastoma line by hy-
perthermic therapy based on gold nanorods, Int. J. Nanomedicine 7 (2012)
1511–1523.
[123] M. Choi, T. Ku, K. Chong, J. Yoon, C. Choi, Minimally invasive molecular delivery
into the brain using optical modulation of vascular permeability, Proc. Natl. Acad.
Sci. U. S. A. 108 (2011) 9256–9261.
[124] R.G. Thorne, C.R. Emory, T.A. Ala, W.H. Frey 2nd, Quantitative analysis of the
olfactory path-way for drug delivery to the brain, Brain Res. 692 (1995) 278–282.
[125] M.T. Shipley, Transport of molecules from nose to brain: Transneuronal ante-
rograde and retrograde labeling in the rat olfactory system by wheat germ ag-
glutinin-horseradish peroxidase applied to the nasal epithelium, Brain Res. Bull.
15 (1985) 129–142.
[126] J.J. Lochhead, R.G. Thorne, Intranasal delivery of biologics to central nervous
system, Adv. Drug Deliv. Rev. 64 (2012) 614–628.
[127] C.D. Chapman, W.H. Frey 2nd, S. Craft, L. Danielyan, M. Hallschmid, H.B. Schiöth,
C. Benedict, Intranasal treatment of central nervous system dysfunction in human,
Pharm. Res. 30 (2012) 2475–2484.
[128] D.A. Leopold, The relationship between nasal anatomy and human olfaction,
Laryngoscope 98 (1988) 1232–1238.
[129] M. Caggiano, J.S. Kauer, D.D. Hunter, Globose basal cells are neuronal progenitors
in the olfactory epithelium: a lineage analysis using a replication-incompetent
retrovirus, Neuron 13 (1994) 339–352.
[130] G. Brand, Olfactory/trigeminal interactions in nasal chemoreception, Neurosci.
Biobehav. Rev. 30 (2006) 908–917.
[131] A. Brodbelt, M. Stoodley, CSF pathways: a review, Br. J. Neurosurg. 21 (2007)
510–520.
[132] A.D. Lorenzo, Electron microscopy of the olfactory and gustatory pathways, Ann.
Otol. Rhinolaryngol. 68 (1960) 410–420.
[133] N.J. Johnson, L.R. Hanson, W.H. Frey, Trigeminal pathways deliver a low mole-
cular weight drug from the nose to the brain and orofacial structures, Mol. Pharm.
7 (2010) 884–893.
[134] R.G. Thorne, G.J. Pronk, V. Padmanabhan, W.H. Frey, Delivery of insulin-like
growth factor-i to the rat brain and spinal cord along olfactory and trigeminal
pathways following intranasal administration, Neuroscience 127 (2004) 481–496.
[135] C.V. Pardeshi, V.S. Belgamwar, Direct nose to brain drug delivery via integrated
nerve pathways bypassing the blood-brain barrier: an excellent platform for brain
targeting, Expert Opin. Drug. Deliv. 10 (2013) 957–972.
[136] M.A. Edeling, C. Smith, D. Owen, Life of a clathrin coated: insight from clathrin
and AP structures, Nat. Rev. Mol. Cell Biol. 7 (2006) 32–44.
[137] J. Rejman, V. Oberle, I.S. Zuhorn, D. Hoekstra, Size dependent internalization of
particles via the pathway of clathrin and caveolae mediated endocytosis, Biochem.
J. 377 (2004) 159–169.
[138] A.T. Jones, Gateways and tools for drug delivery: endocytic pathway and the
cellular dynamics of cell penetrating peptides, Int. J. Pharm. 354 (2008) 34–38.
[139] C.M. Van Itallie, J.M. Anderson, Claudins and epithelial paracellular transport,
Annu. Rev. Physiol. 68 (2006) 403–429.
[140] M. Miyamoto, H. Natsume, I. Satoh, K. Ohtake, M. Yamaguchi, D. Kobayashi,
K. Sugibayashi, Y. Morimoto, Effect of poly–L-arginine on the nasal absorption of
FTIR-dextran of different molecular weights and recombinant human granulocyte
colony stimulating factor (RHG-SF) in rats, Int. J. Pharm. 226 (2001) 127–138.
[141] A. Yamamoto, T. Iseki, M. Ochi-Sugiyama, N. Okada, T. Fujita, S. Muranishi, J.
Control. Release 76 (2001) 363–374.
[142] M. Hinchcliffe, L. Illum, Intranasal insulin delivery and therapy, Adv. Drug Deliv.
A.R. Khan et al.
Rev. 35 (1999) 199–234.
[143] S. Dey, B. Mahanti, B. Mazumder, A. Malgope, S. Dasgupta, Nasal drug delivery: an
approach of drug delivery through nasal route, Der Pharmac. Sin. 2 (2011)
94–106.
[144] X.A. Si, J. Xi, J. Kim, Y. Zhou, H. Zhong, Modeling of release position and venti-
lation effects on olfactory aerosol drug delivery, Respir. Physiol. Neurobiol. 186
(2013) 22–32.
[145] A.J. Guastella, I.B. Hickie, M.M. Mcguinness, M. Otis, E.A. Woods, H.M. Disinger,
H.K. Chan, T.F. Chen, R.B. Banati, Recommendations for the standardisation of
oxytocin nasal administration and guidelines for its reporting in human, research,
Psychoneuroendocrinology 38 (2013) 612–625.
[146] R.J. Soane, M. Frier, A.C. Perkins, N.S. Jones, S.S. Davis, L. Illum, Evaluation of the
clearance characteristics of bioadhesive systems in humans, Int. J. Pharm. 178
(1999) 55–65.
[147] F.W. Merkus, J.C. Verhoef, N.G. Schipper, E. Marttin, Nasal mucociliary clearance
as a factor in nasal drug delivery, Adv. Drug Deliv. Rev. 29 (1998) 13–38.
[148] E.L. Smith, R.L. Hill, A. Borman, Activity of insulin degraded by leucine amino-
peptidase, Biochem. Biophys. Acta 29 (1958) 207–214.
[149] V.H. Lee, A. Yamamoto, Penetration and enzymatic barriers to peptide and protein
absorption, Adv. Drug Deliv. Rev. 4 (1990) 171–207.
[150] P. Cole, The four components of the nasal valve, Am. J. Rhinol. 17 (2003)
107–110.
[151] L.L. Wearly, Recent progress in protein and peptide delivery by non-invasive
routes, Crit. Rev. Ther. Drug Carrier Syst. 8 (1991) 331–394.
[152] R. Smolnik, M. Molle, H.L. Fehm, J. Born, Brain potential and attention after acute
subchronic intranasal administration of ACTH4-10 desacetyl-a-MSH in human,
Neuroendocrinology 70 (1999) 63–72.
[153] X.F. Liu, J.R. Fawcett, R.G. Thorn, T.A. Defor, W.H. Frey, Intranasal administration
of insulin like growth factor-I bypass the blood brain barrier and protects against
focal cerebral ischemic damage, J. Neurol. Sci. 187 (2001) 91–97.
[154] L. Danielyan, R. Schafer, A. von Ameln-Mayerhofer, M. Buadze, J. Geisler,
T. Klopfer, U. Burkhardt, B. Proksch, S. Verleysdonk, M. Ayturan, G.H. Buniatian,
C.H. Gleiter, W.H. Frey 2nd, Intranasal delivery of cells to brain, Eur. J. Cell Biol.
88 (2009) 315–324.
[155] M. Reitz, M. Demestre, J. Sedlacik, H. Meissner, J. Fiehler, S.U. Kim, M. Westphal,
N.O. Schmidt, Intranasal delivery of neural stem/progenitor cells: a non-invasive
passage to target intracerebral gioma, Stem Cells Transl. Med. 1 (2012) 866–873.
[156] I.V. Balyasnikova, M.S. Prasol, S.D. Ferguson, Y. Han, A.U. Ahmed, M. Gutova,
A.L. Tobias, D. Mustafi, E. Rincón, L. Zhang, K.S. Aboody, M.S. Lesniak, Intranasal
delivery of mesenchymal stem cells significantly extends survival of irradiated
mice with experimental brain tumors, Mol. Ther. 22 (2014) 140–148.
[157] C.A. Fonseca, R.M. Teixeira, R. Ramina, G. Kovaleski, J.T. Silva, J. Nagel,
T. Quirico-Santos, Case of advanced recurrent glioblastoma successfully treated
with monoterpene perillyl alcohol by intranasal administration, J. Cancer Ther. 2
(2011) 16–21.
[158] K. Ozduman, G. Wollmann, J.M. Piepmeier, A. van den Pol, Systemic vesicular
stomatitis virus selectively destroys multifocal glioma and metastatic carcinoma in
brain, J. Neurosci. 28 (2008) 1882–1893.
[159] T. Shingaki, D. Inoue, T. Furubayashi, T. Sakane, H. Katsumi, A. Yamamoto,
S. Yamashita, Intranasal delivery of methotrexate to brain tumors in rat: new
strategy for brain tumor chemotherapy, Mol. Pharm. 7 (2010) 1561–1568.
[160] R. Hashizume, T. Ozawa, S.M. Gryaznov, A.W. Bollen, K.R. Lamborn, W.H. Frey
2nd, D.F. Deen, New therapeutic approach for brain tumors: intranasal delivery of
telomerase inhibitor GRN163, Neuro-Oncology 10 (2008) 112–120.
[161] X. Song, L. Xie, X. Wang, Q. Zeng, T.C. Chen, W. Wang, X. Song, Temozolomide-
perillyl alcohol conjugate induced reactive oxygen species accumulation con-
tributes to its cytotoxicity against non-small cell lung cancer, Sci. Rep. 6 (2016)
(Article number: 22762).
[162] T.C. Chen, H.Y. Cho, W. Wang, M. Barath, N. Sharma, F.M. Hofman,
A.H. Schönthal, A novel temozolomide-perillyl alcohol conjugate exhibits superior
activity against breast cancer cells in vitro and intracranial triple-negative tumor
growth in vivo, Mol. Cancer Ther. 13 (2014) 1181–1193.
[163] M.A. Reger, G.S. Watson, W.H. Frey 2nd, L.D. Baker, B. Cholerton, M.L. Keeling,
D.A. Belongia, M.A. Fishel, S.R. Plymate, G.D. Schellenberg, M.M. Cherrier,
S. Craft, Effects of intranasal insulin on cognition in memory-impaired older
adults: modulation by APOE genotype, Neurobiol. Aging 27 (2006) 451–458.
[164] M.A. Reger, G.S. Watson, P.S. Green, L.D. Baker, B. Cholerton, M.A. Fishel,
S.R. Plymate, M.M. Cherrier, G.D. Schellenberg, W.H. Frey 2nd, S. Craft, Intranasal
insulin administration dose-dependently modulates verbal memory and plasma
amyloid-beta in memory-impaired older adults, J. Alzheimers Dis. 13 (2008)
323–331.
[165] A.J. Guastella, S.L. Einfeld, K.M. Gray, N.J. Rinehart, B.J. Tonge, T.J. Lambert,
I.B. Hickie, Intranasal oxytocin improves emotion recognition for youth with
autism spectrum disorders, Biol. Psychiatry 67 (2010) 692–694.
[166] P.C. Baier, S.L. Weinhold, V. Huth, B. Gottwald, R. Ferstl, D. Hinze-Selch,
Olfactory dysfunction in patients with narcolepsy with cataplexy is restored by
intranasal Orexin A (Hypocretin-1), Brain 131 (2008) 2734–2741.
[167] C. Schulz, K. Paulus, O. Jöhren, H. Lehnert, Intranasal leptin reduces appetite and
induces weight loss in rats with diet-induced obesity (DIO), Endocrinology 153
(2012) 143–153.
[168] S. Fliedner, C. Schulz, H. Lehnert, Brain uptake of intranasally applied radio-
iodinated leptin in Wistar rats, Endocrinology 47 (2006) 2088–2094.
[169] T. Fişgin, Y. Gurer, T. Tezic, N. Senbil, P. Zorlu, C. Okuyaz, D. Akgün, Effects of
intranasal midazolam and rectal diazepam on acute convulsions in children:
prospective randomized study, J. Child Neurol. 17 (2002) 123–126.
[170] G.J. Haan, P. van der Geest, G. Doelman, E. Bertram, P. Edelbroek, A comparison
of midazolam nasal spray and diazepam rectal solution for the residential treat-
ment of seizure exacerbations, Epilepsia 51 (2010) 478–482.
[171] H. Ashton, Z. Hassan, Best evidence topic report. Intranasal naloxone in suspected
opioid overdose, Emerg Med 23 (2006) 221–223.
[172] H.Y. Cho, W. Wang, N. Jhaveri, S. Torres, J. Tseng, M.N. Leong, D.J. Lee,
387
Journal of Controlled Release 268 (2017) 364–389
A. Goldkorn, T. Xu, N.A. Petasis, S.G. Louie, A.H. Schönthal, F.M. Hofman,
T.C. Chen, Perillyl alcohol for the treatment of temozolomide-resistant gliomas,
Mol. Cancer Ther. 11 (2012) 2462–2472.
[173] L. Illum, Nasal drug delivery–possibilities, problems and solutions, J. Control.
Release 87 (2003) 187–198.
[174] R.M. Mainardes, M.C. Urban, P.O. Cinto, M.P. Gremiao, Liposomes and micro/
nanoparticles as colloidal carriers for nasal drug delivery, Curr. Drug Deliv. 3
(2006) 275–285.
[175] L. Illum, Nanoparticle systems for nasal delivery of drugs: a real improvement over
simple systems? J. Pharm. Sci. 96 (2006) 473–483.
[176] F. Chen, Z.R. Zhang, F. Yuan, X. Qin, M. Wang, Y. Huang, In vitro and in vivo study
of N-trimethyl chitosan nanoparticles for oral protein delivery, Int. J. Pharm. 349
(2008) 226–233.
[177] A. Dalpiaz, E. Gavini, G. Colombo, P. Russo, F. Bortolotti, L. Ferraro, S. Tanganelli,
A. Scatturin, E. Menegatti, P. Giunchedi, Brain uptake of an anti-ischemic agent by
nasal administration of microparticles, J. Pharm. Sci. 97 (2008) 4889–4903.
[178] A. Des Rieux, E.G. Ragnarsson, E. Gullberg, V. Preat, Y.J. Schneider, P. Artursson,
Nanoparticles across an in vitro model of the human follicle associated epithelium,
Eur. J. Pharm. Sci. 25 (2005) 455–465.
[179] Y. Huang, M.D. Donovan, Microsphere transport pathways in the rabbit nasal
mucosa, Int. J. Pharm. Adv. 1 (1996) 298–309.
[180] A. Bernkop-Schnurch, S. Dunnhaupt, Chitosan-based drug delivery systems, Eur. J.
Pharm. Biopharm. 81 (2012) 463–469.
[181] M. Garcia-Fuentes, M.J. Alonso, Chitosan-based drug nanocarriers: where do we
stand? J. Control. Release 161 (2012) 496–504.
[182] D. Mittal, S. Md, Q. Hasan, M. Fazil, A. Ali, S. Baboota, J. Ali, Brain targeted
nanoparticulate drug delivery system of rasagiline via intranasal route, Drug
Deliv. (1) (2016) 130–139.
[183] S. Md, R.A. Khan, G. Mustafa, K. Chuttani, S. Baboota, J.K. Sahni, J. Ali,
Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain
delivery: Pharmacodynamic, pharmacokinetic and scintigraphy study in mice
model, Eur. J. Pharm. Sci. 48 (2012) 393–405.
[184] M. Tafaghodi, S. Abolghasem Sajadi Tabassi, M.R. Jaafari, S.R. Zakavi, M. Momen-
Nejad, Evaluation of the clearance characteristics of various microspheres in the
human nose by gamma-scintigraphy, Int. J. Pharm. 280 (2004) 125–135.
[185] H.K. Makadia, S.J. Siegel, Poly lactic-co-glycolic acid (PLGA) as biodegradable
controlled drug delivery carrier, Polymer 3 (2011) 1377–1397.
[186] T. Musumeci, R. Pellitteri, M. Spatuzza, G. Puglisi, Nose-to-brain delivery: eva-
luation of polymeric nanoparticles on olfactory ensheathing cells uptake, J.
Pharm. Sci. 103 (2014) 628–635.
[187] Z. Wen, Z. Yan, K. Hu, Z. Pang, X. Cheng, L. Guo, Q. Zhang, X. Jiang, L. Fang,
R. Lai, Odorranalectin-conjugated nanoparticles: preparation, brain delivery and
pharmacodynamic study on Parkinson's disease following intranasal administra-
tion, J. Control. Release 151 (2011) 131–138.
[188] M. Elfinger, C. Maucksch, C. Rudolph, Characterization of lactoferrin as a tar-
geting ligand for nonviral gene delivery to airway epithelial cells, Biomaterials 28
(2007) 3448–3455.
[189] C. Bi, A. Wang, Y. Chu, S. Liu, H. Mu, W. Liu, Z. Wu, K. Sun, Y. Li, Intranasal
delivery of rotigotine to the brain with lactoferrin-modified PEG-PLGA nano-
particles for Parkinson's disease treatment, Int. J. Nanomedicine 11 (2016)
6547–6559.
[190] Y.K. Katare, R.P. Daya, G.C. Sookram, R.E. Luckham, J. Bhandari, A.S. Chauhan,
R.K. Mishra, Brain targeting of a water insoluble antipsychotic drug haloperidol
via the intranasal route using PAMAM dendrimers, Mol. Pharm. 12 (2015)
3380–3388.
[191] I.D. Kim, J.H. Shin, S.W. Kim, S. Choi, J. Ahn, P.L. Han, J.S. Park, J.K. Lee,
Intranasal delivery of HMGB1 siRNA confers target gene knockdown and robust
neuroprotection in the postischemic brain, Mol. Ther. 20 (2012) 829–839.
[192] T.T. Win-Shwe, H. Sone, Y. Kurokawa, Y. Zeng, Q. Zeng, H. Nitta, S. Hirano,
Effects of PAMAM dendrimers in the mouse brain after a single intranasal in-
stillation, Toxicol. Lett. 228 (2014) 207–215.
[193] T. Lin, E. Liu, H. He, M.C. Shin, C. Moon, V.C. Yang, Y. Huang, Nose-to-brain
delivery of macromolecules mediated by cell-penetrating peptides, Acta Pharm.
Sin. B 6 (2016) 352–358.
[194] H. Xia, X. Gao, G. Gu, Z. Liu, N. Zeng, Q. Hu, Q. Song, L. Yao, Z. Pang, X. Jiang,
J. Chen, H. Chen, Low molecular weight protamine functionalized nanoparticles
for drug delivery to the brain after intranasal administration, Biomaterials 32
(2011) 9888–9898.
[195] N. Kamei, M. Takeda-Morishita, Brain delivery of insulin boosted by intranasal
coadministration with cell-penetrating peptides, J. Control. Release 197 (2015)
105–110.
[196] E. Mattiuz, R. Franklin, T. Gillespie, A. Murphy, J. Bernstein, A. Chiu, T. Hotten,
K. Kassahun, Disposition and metabolism of olanzapine in mice, dogs, and rhesus
monkeys, Drug Metab. Dispos. 25 (1997) 573–583.
[197] S. Md, M. Ali, S. Baboota, J.K. Sahni, A. Bhatnagar, J. Ali, Preparation, char-
acterization, in vivo biodistribution and pharmacokinetic studies of donepezil-
loaded PLGA nanoparticles for brain targeting, Drug Dev. Ind. Pharm. 40 (2014)
278–287.
[198] C. Zhang, J. Chen, C. Feng, X. Shao, Q. Liu, Q. Zhang, Z. Pang, X. Jiang, Intranasal
nanoparticles of basic fibroblast growth factor for brain delivery to treat
Alzheimer's disease, Int. J. Pharm. (1–2) (2014) 192–202.
[199] Q. Liu, Y. Shen, J. Chen, X. Gao, C. Feng, L. Wang, Q. Zhang, X. Jiang, Nose to
brain transport pathway of wheat germ agglutinin conjugated PEG-PLA nano-
particles, Pharm. Res. 29 (2012) 546–558.
[200] L. Yan, W. Huiyuan, Y. Jiang, Y. Huang, Cell-penetrating peptide-modified PLGA
nanoparticles for enhanced nose-to-brain macromolecular delivery, Macromol.
Res. 21 (2013) 435–441.
[201] B. Shah, D. Khunt, H. Bhatt, M. Misra, H. Padh, Application of quality by design
approach for intranasal delivery of rivastigmine loaded solid lipid nanoparticles:
effect on formulation and characterization parameters, Eur. J. Pharm. Sci. 78
(2015) 54–66.
A.R. Khan et al.
[202] Y.Z. Zhao, X. Li, C.T. Lu, M. Lin, L.J. Chen, Q. Xiang, M. Zhang, P.R. Jin, X. Jiang,
X.T. Shen, X.K. Li, J. Cai, Gelatin nanostructured lipid carriers-mediated intranasal
delivery of basic fibroblast growth factor enhances functional recovery in hemi-
parkinsonian rats, Nanomedicine 10 (2014) 755–764.
[203] R.H. Müller, M. Radtke, S.A. Wissing, Nanostructured lipid matrices for improved
microencapsulation of drugs, Int. J. Pharm. 242 (2002) 121–128.
[204] T.B. Devkar, A.R. Tekade, K.R. Khandelwal, Surface engineered nanostructured
lipid carriers for efficient nose to brain delivery of ondansetron HCl using Delonix
regia gum as a natural mucoadhesive polymer, Colloids Surf. B: Biointerfaces 122
(2014) 143–150.
[205] O. Gartziandia, E. Herran, J.L. Pedraz, E. Carro, M. Igartua, R.M. Hernandez,
Chitosan coated nanostructured lipid carriers for brain delivery of proteins by
intranasal administration, Colloids Surf. B: Biointerfaces 134 (2015) 304–313.
[206] S. Yadav, F. Gattacceca, R. Panicucci, M.M. Amiji, Comparative biodistribution
and pharmacokinetic analysis of cyclosporine-A in the brain upon intranasal or
intravenous administration in an oil-in-water nanoemulsion formulation, Mol.
Pharm. 2 (2015) 1523–1533.
[207] Z. Ding, Y. Zhang, N. Wen, Z. Sun, C. Li, B. Zhang, W/O nanoemulsion-based
intranasal drug delivery system of Panax notoginseng saponins for brain targeting,
J. Control. Release 213 (2015) e8–e152.
[208] S. Sood, K. Jain, K. Gowthamarajan, Optimization of curcumin nanoemulsion for
intranasal delivery using design of experiment and its toxicity assessment, Colloids
Surf. B 113 (2014) 330–337.
[209] S. Yadav, S.K. Gandham, R. Panicucci, M.M. Amiji, Intranasal brain delivery of
cationic nanoemulsion-encapsulated TNFα siRNA in prevention of experimental
neuroinflammation, Nanomed. Nanotechnol. 12 (2016) 987–1002.
[210] R.H. Parikh, R.J. Patel, Nanoemulsions for intranasal delivery of riluzole to im-
prove brain bioavailability: formulation development and pharmacokinetic stu-
dies, Curr. Drug Deliv. 13 (2016) 1130–1143.
[211] R. Jain, S. Nabekar, P. Dandekar, V. Patravale, Micellar nanocarriers: potential
nose-to-brain delivery of zolmitriptan as novel migraine therapy, Pharm. Res. 27
(2010) 655–664.
[212] T. Kanazawa, H. Taki, K. Tanaka, Y. Takashima, H. Okada, Cell penetrating pep-
tide-modified block copolymer micelles promote direct brain delivery via in-
tranasal administration, Pharm. Res. 28 (2011) 2130–2139.
[213] T. Kanazawa, F. Akiyama, S. Kakizaki, S. Takashima, Y. Seta, Delivery of siRNA to
the brain using a combination of nose-to-brain delivery and cell-penetrating
peptide-modified nano-micelles, Biomaterials 34 (2013) 9220–9226.
[214] H. Taki, T. Kanazawa, F. Akiyama, Y. Takashima, H. Okada, Intranasal delivery of
–loaded Tat-modified nanomicells for treatment of intracranial brain tumors,
Pharmaceutics 5 (2012) 1092–1102.
[215] S. Shelke, S. Shahi, S. Jalalpure, D. Dhamecha, S. Shengule, Formulation and
evaluation of thermoreversible mucoadhesive in-situ gel for intranasal delivery of
naratriptan hydrochloride, J. Drug Deliv. Sci. Technol. 29 (2015) 238–244.
[216] A.P. Perez, C. Mundina-Weilenmann, E.L. Romero, M.J. Morilla, Increased brain
radioactivity by intranasal P-labeled siRNA dendriplexes within in situ-forming
mucoadhesive gels, Int. J. Nanomedicine 7 (2012) 1373–1385.
[217] J. Hao, J. Zhao, S. Zhang, T. Tong, Q. Zhuang, K. Jin, W. Chen, H. Tang,
Fabrication of an ionic-sensitive in situ gel loaded with resveratrol nanosuspen-
sions intended for direct nose-to-brain delivery, Colloids Surf. B: Biointerfaces 147
(2016) 376–386.
[218] S. Khan, K. Patil, N. Bobade, P. Yeole, R. Gaikwad, Formulation of intranasal
mucoadhesive temperature-mediated in situ gel containing ropinirole and eva-
luation of brain targeting efficiency in rats, J. Drug Target. 18 (2010) 223–234.
[219] R.j. Babu, P.P. Dayal, K. Pawar, M. Singh, Nose-to-brain transport of melatonin
from polymer gel suspensions: a microdialysis study in rats, J. Drug Target. 19
(2011) 731–740.
[220] V.P. Torchilin, Liposomes as targetable drug carriers, Crit. Rev. Ther. Drug Carrier
Syst. 2 (1985) 65–115.
[221] V.P. Torchilin, Recent advances with liposomes as pharmaceutical carriers, Nat.
Rev. Drug Discov. 4 (2005) 145–160.
[222] X. Zheng, X. Shao, C. Zhang, Y. Tan, Q. Liu, X. Wan, Q. Zhang, S. XU, X. Jiang,
Intranasal H102 peptide loaded liposomes for brain delivery to treat Alzheimer's
disease, Pharm. Res. 32 (2015) 3837–3849.
[223] R. Narayan, M. Singh, O. Ranjan, Y. Nayak, S. Garg, G.V. Shavi, U.Y. Nayak,
Development of risperidone liposomes for brain targeting through intranasal
route, Life Sci. 163 (2016) 38–45.
[224] S. Samudre, A. Tekade, K. Thorve, Xanthan gum coated mucoadhesive liposomes
for efficient nose to brain delivery of curcumin, Drug Deliv. Lett. 5 (2016)
201–207.
[225] Z. Yang, Y.Q. Zhang, Z.Z. Wang, K. Wu, J.N. Lou, X.R. Qi, Enhanced brain dis-
tribution and pharmacodynamics of rivastigmine by liposomes following in-
tranasal administration, Int. J. Pharm. 452 (2013) 344–354.
[226] A. Pal, S. Gupta, A. Jaiswal, A. Dube, S.P. Vyas, Development and evaluation of
tripalmitin emulsomes for the treatment of experimental visceral leishmaniasis, J.
Liposome Res. 22 (2012) 62–71.
[227] R. Paliwal, S.R. Paliwal, N. Mishra, A. Mehta, S.P. Vyas, Engineered chylomicron
mimicking carrier emulsome for lymph targeted oral delivery of methotrexate, Int.
J. Pharm. 380 (2009) 181–188.
[228] N. Aswathy, M. Vidhya, R. Saranya, R. Sreelakshmy, N. Sreeja, Emulsomes: a novel
liposoomal formulation for sustained drug delivery, Int. Res. J. Pharm. 3 (2013)
192–196.
[229] G.M. El-Zaafarany, M.E. Soliman, S. Mansour, G.A. Awad, Identifying lipidic
emulsomes for improved oxcarbazepine brain targeting: in vitro and rat in vivo
studies, Int. J. Pharm. 503 (2016) 127–140.
[230] E. Gavini, G. Rassu, L. Ferraro, S. Beggiato, A. Alhalaweh, S. Velaga, N. Marchett,
P. Bandiera, P. Giunchedi, A. Dalpiaz, Influence of polymeric microcarriers on the
in vivo intranasal uptake of an anti-migraine drug for brain targeting, Eur. J.
Pharm. Biopharm. 0 (2013) 174–183.
[231] Y.S. Choi, D.Y. Cho, H.K. Lee, J.K. Cho, D.H. Lee, Y.H. Bae, J.K. Lee, H.C. Kang,
Enhanced cell survival of pH-sensitive bioenergetic nucleotide nanoparticles in
388
Journal of Controlled Release 268 (2017) 364–389
energy/oxygen-depleted cells and their intranasal delivery for reduced brain in-
farction, Acta Biomater. 41 (2016) 147–160.
[232] H.D. Rosas, Y.I. Chen, G. Doros, D.H. Salat, N.K. Chen, K.K. Kwong, A. Bush,
J. Fox, S.M. Hersch, Alterations in brain transition metals in Huntington disease:
an evolving and intricate story, Arch. Neurol. 69 (2012) 887–893.
[233] J. Chen, E. Marks, B. Lai, Z. Zhang, J.A. Duce, L.Q. Lam, I. Volitakis, A.I. Bush,
S. Hersch, J.H. Fox, Iron accumulates in Huntington's disease neurons: protection
by deferoxamine, PLoS One 8 (2013) e77023.
[234] R.M. Rival, D.S. Page, T.J. Chandraratna, E. Sendall, B. Ryder, H. Liu, T. Lewis,
R. Rosahl, L.M. Hider, M.S. Camargo, D.C. Shearman, D.A. Crowther, D.A. Lomas,
Fenton, chemistry and oxidative stress mediate the toxicity of the beta-amyloid
peptide in a Drosophila model of Alzheimer's disease, Eur. J. Neurosci. 29 (2009)
1335–1347.
[235] J.M. Fine, A.C. Forsberg, D.B. Renner, K.A. Faltesek, K.G. Mohan, J.C. Wong,
L.C. Arneson, J.W. Crow, W.H. Frey II, L.R. Hanson, Intranasally-administered
deferoxamine mitigates toxicity of 6-OHDA in a rat model of Parkinson's disease,
Brain Res. 1574 (2014) 96–104.
[236] G. Rassu, E. Soddu, M. Cossu, A. Brundu, G. Cerri, N. Marchetti, L. Ferraro,
R.F. Regan, P. Giunchedi, E. Gavini, A. Dalpiaz, Solid microparticles based on
chitosan or methyl-β-cycl-odextrin: a first formulative approach to increase the
nose-to-brain transport of deferoxamine mesylate, J. Control. Release 201 (2015)
68–77.
[237] S. Desai, G. Vidyasagar, A. Bhandhari, Evaluation of brain targeting for the nasal
delivery of midazolam, Int. J. Pharm. Sci. Rev. Res. 12 (2012) 109–113.
[238] S. Jose, C.R. Ansa, T.A. Cinu, A.J. Chacko, N.A. Aleykutty, S.V. Ferreira,
E.B. Souto, Thermo-sensitive gels containing lorazepam microspheres for in-
tranasal brain targeting, Int. J. Pharm. 441 (2013) 516–526.
[239] S. Lungare, K. Hallam, R.K. Badhan, Phytochemical-loaded mesoporous silica
nanoparticles for nose-to-brain olfactory drug delivery, Int. J. Pharm. 513 (2016)
280–293.
[240] G.A. Abdelbary, M.I. Tadros, Brain targeting of olanzapine via intranasal delivery
of core–shell difunctional block copolymer mixed nanomicellar carriers: in vitro
characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution
studies, Pharm. Nanotech. 452 (2013) 300–310.
[241] M. Kumar, K. Pathak, A. Mishra, Formulation and characterization of nanoemul-
sion based drug delivery system of risperidone, Drug Dev. Ind. Pharm. 35 (2009)
387–395.
[242] S. Haque, S. Md, M. Fazil, M. Kumar, J.K. Sahni, J. Ali, S. Baboota, Venlafaxine
loaded chitosan NPs for brain targeting: pharmacokinetic and pharmacodynamic
evaluation, Carbohydr. Polym. 89 (2012) 72–79.
[243] L.R. Hanson, J.M. Fine, J.D. Hoekman, T.M. Nguyen, R.B. Burns, P.M. Martinez,
J. Pohl, W.H. Frey 2nd, Delivery of growth differentiation factor 5 to the central
nervous system, Drug Deliv. 19 (2012) 149–154.
[244] A. Shahiwala, D. Dash, Preparation and evaluation of microemulsion based for-
mulation for rapid onset intranasal delivery of zonisamide, Adv. Sci. Lett. 3 (2010)
442–446.
[245] D. Sharma, R.K. Sharma, A. Bhatnagar, D.K. Nishad, T. Singh, R. Gabrani,
S.K. Sharma, J. Ali, S. Dang, Nose to brain delivery of midazolam loaded PLGA
nanoparticles: in vitro and in vivo investigations, Curr. Drug Deliv. 13 (2016)
557–564.
[246] M. Kumar, A. Misra, A.K. Babbar, A.K. Mishra, P. Mishra, K. Pathak, Intranasal
nanoemulsion based brain targeting drug delivery system of risperidone, Int. J.
Pharm. 358 (2008) 285–291.
[247] S. Eskandari, J. Varshosaz, M. Minaiyan, M. Tabbakhian, Brain delivery of valproic
acid via intranasal administration of nanostructured lipid carriers: in vivo phar-
macodynamic studies using rat electroshock model, Int. J. Nanomedicine 6 (2011)
363–371.
[248] X. Wang, N. Chi, X. Tang, Preparation of estradiol chitosan nanoparticles for im-
proving nasal absorption and brain targeting, Eur. J. Pharm. Biopharm. 70 (2008)
735–740.
[249] C. Benedict, M. Hallschmid, A. Hatke, B. Schultes, H.L. Fehm, J. Born, W. Kern,
Intranasal insulin improves memory in humans, Psychoneuroendocrinology 29
(2004) 1326–1334.
[250] A.N. Laza, S. Mourtas, I. Youssef, C. Parizot, A. Dauphin, B. Delatour,
S.G. Antimisiaris, C. Duyckaerts, Curcumin-conjugated nanoliposomes with high
affinity for Aβ deposits: possible applications to Alzheimer disease, Nanomed.
Nanotechnol. 9 (2013) 712–721.
[251] A. Bonaccorso, T. Musumeci, M.F. Serapide, R. Pellitteri, I.F. Uchegbu, G. Puglisi,
Nose to brain delivery in rats: effect of surface charge of rhodamine B labeled
nanocarriers on brain subregion localization, Colloids Surf. B: Biointerfaces 1
(2017) 297–306.
[252] B. Jansson, E. Björk, Visualization of in vivo olfactory uptake and transfer using
fluorescein dextran, J. Drug Target. 10 (2002) 379–386.
[253] T. Kanazawa, H. Taki, K. Tanaka, Y. Takashima, H. Okada, Cell-penetrating pep-
tide-modified block copolymer micelles promote direct brain delivery via in-
tranasal administration, Pharm. Res. 28 (9) (2011) 2130.
[254] N.G. Schipper, K.M. Varum, P. Artursson, Chitosans as absorption enhancers for
poorly absorbable drugs. 1: influence of molecular weight and degree of acetyla-
tion on drug transport across human intestinal epithelial (Caco-2) cells, Pharm.
Res. 13 (1996) 1686–1692.
[255] T. Aspden, L. Illum, O. Skaugrud, The effect of chronic nasal application of chit-
osan solutions on cilia beat frequency in guinea pigs, Int. J. Pharm. 153 (1997)
137–146.
[256] N. Haffejee, J. Du Plessis, D.G. Muller, C. Schultz, A.F. Kotze, C. Goosen, Intranasal
toxicity of selected absorption enhancers, Pharmazie 56 (2001) 882–888.
[257] S.R.K. Vaka, S.N. Murthy, M.A. Repka, T. Nagy, Upregulation of endogenous
neurotrophin levels in the brain by intranasal administration of carnosic acid, J.
Pharm. Sci. 100 (2011) 3139–3145.
[258] H. Bshara, R. Osman, S. Mansour, Ael-H. El-Shamy, Chitosan and cyclodextrin in
intranasal microemulsion for improved brain buspirone hydrochloride pharma-
cokinetics in rats, Carbohydr. Polym. 99 (2014) 297–305.
A.R. Khan et al.
[259] D. Vllasaliu, R. Exposito-Harris, A. Heras, L. Casettari, M. Garnett, L. Illum,
S. Stolnik, Tight junction modulation by chitosan nanoparticles: comparison with
chitosan solution, Int. J. Pharm. 400 (2010) 183–193.
[260] S. Md, S. Haque, M. Fazil, M. Kumar, S. Baboota, J.K. Sahni, J. Ali, Optimised
nanoformulation of bromocriptine for direct nose-to-brain delivery: biodistribu-
tion, pharmacokinetic and dopamine estimation by ultra-HPLC/mass spectrometry
method, Expert Opin. Drug. Deliv. 11 (2014) 827–842.
[261] X. Gao, W. Tao, W. Lu, Q. Zhang, Y. Zhang, X. Jiang, S. Fu, Lectin-conjugated
PEG–PLA nanoparticles: preparation and brain delivery after intranasal adminis-
tration, Biomaterials 27 (2006) 3482–3490.
[262] K. Kilk, R. Mahlapuu, U. Soomets, U. Langel, Analysis of in vitro toxicity of five
cell-penetrating peptides by metabolic profiling, Toxicology 265 (2009) 87–95.
[263] E. Koren, V.P. Torchilin, Cell-penetrating peptides: breaking through to the other
side, Trends Mol. Med. 18 (2012) 385–393.
[264] S. Patel, B. Patel, Z. Patel, C.V. Pardeshi, Nanocarriers as novel nose-to-brain
targeted drug delivery platforms, Indian J. Nov. Drug Deliv 4 (2012) 243–251.
[265] G.A. Abdelbary, M.I. Tadros, Brain targeting of olanzapine via intranasal delivery
of core-shell difunctional block copolymer mixed nanomicellar carriers: in-vitro
characterization, ex-vivo estimation of nasal toxicity and in-vivo biodistribution
studies, Int. J. Pharm. 452 (16) (2013).
[266] P. Upadhyay, J. Trivedi, K. Pundarikakshudu, N. Sheth, Direct and enhanced de-
livery of nanoliposomes of anti schizophrenic agent to the brain through nasal
rout, Saudi Pharm. J. 25 (2017) 346–358.
[267] G. Rassu, E. Soddu, M. Cossu, E. Gavini, P. Giunchedi, A. Dalpiaz, Particulate
formulations based on chitosan for nose-to-brain delivery of drugs. A review, J.
Drug Deliv. Sci. Technol. (2016) 77–87.
[268] J.D. Suman, B.L. Laube, R. Dalby, Comparison of nasal deposition and clearance of
aerosol generated by nebulizer and an aqueous spray pump, Pharm. Res. 16
(1999) 1648.
[269] P.G. Djupesland, A. Skretting, M. Winderen, T. Holand, Bi-directional nasal de-
livery of aerosols can prevent lung deposition, J. Aerosol. Med. 17 (2004) 249.
[270] P.G. Djupesland, Nasal drug delivery devices: characteristics and performance in a
clinical perspective—a review, Drug Deliv. Transl. Res. 3 (2013) 42–62.
[271] P.G. Djupesland, J.C. Messina, R.A. Mahmoud, Nasal approach to delivering
treatment for brain disease: an anatomic, physiologic and delivery technology
overview, Ther. Deliv. 5 (2014) 709–733.
[272] Optinose, OptiNose to Present at the 34th Annual J.P. Morgan Healthcare
Conference, http://www.optinose.com/press-releases/optinose-to-present-at-the-
34th-annual-j-p-organ-healthcare-conference.
[273] D.S. Quintana, L.T. Westlye, Q.G. Rustan, N. Tesli, C.L. Poppy, H. Smevik, M. Tesli,
M. Røine, R.A. Mahmoud, K.T. Smerud, P.G. Djupesland, O.A. Andreassen, Low-
dose oxytocin delivered intranasally with Breath Powered device affects social-
cognitive behavior: a randomized four-way crossover trial with nasal cavity di-
mension assessment, Transl. Psychiatry 5 (2015) e602.
[274] Optinose, OptiNose® Announces Pipeline Project to Evaluate Nose- to-Brain
Application of Bi-Directional™ Breath Powered® Technology Selected for
Norwegian Government Funding, http://www.optinose.com/press-releases/
optinose-announces-pipeline-project-to-evaluate-nose-to-brain-application-of-bi-
directional-breath-powered-technology-selected-for-norwegian-government-
funding, (2016).
[275] M. Pozzoli, P. Rogueda, B. Zhu, T. Smith, P.M. Young, D. Traini, F. Sonvico, Dry
powder nasal drug delivery: challenges, opportunities and a study of the com-
mercial Teijin Puvlizer Rhinocort® device and formulation, Drug Dev. Ind. Pharm.
42 (2016) 1660–1668.
[276] Platform technology. http://www.SNBL.com.
[277] S. Haruta, T. Tsutsui, Meeting the needs for nasal delivery devices for powder
formulations, Drug Dev. Deliv. 12 (2012) 22–27.
[278] R.S. Kaye, T.S. Purewal, O.H. Alpar, Development and testing of particulate for-
mulations for the nasal delivery of antibodies, J. Control. Release 135 (2009)
127–135.
[279] J. Huanga, R.J. Garmise, T.M. Crowder, K. Mara, C.R. Hwanga, A.J. Hickey,
J.A. Mikszta, V.J. Sullivana, A novel dry powder influenza vaccine and intranasal
delivery technology: induction of systemic and mucosal immune responses in rats,
Vaccine 23 (2004) 794–801.
[280] W.E. Berger, J.W. Godfrey, A.L. Slater, Intranasal corticosteroids: the development
of a drug delivery device for fluticasone furoate as a potential step toward im-
proved compliance, Expert Opin. Drug. Deliv. 4 (2007) 689–701.
[281] M. Penttilä, P. Poulsen, K. Hollingworth, M. Holmström, Dose-related efficacy and
tolerability of fluticasone propionate nasal drops 400 μg once daily and twice daily
389
Journal of Controlled Release 268 (2017) 364–389
in the treatment of bilateral nasal polyposis: a placebo-controlled randomized
study in adult patients, Clin. Exp. Allergy 30 (2000) 94–102.
[282] P. Merkus, F.A. Ebbens, B. Muller, W.J. Fokkens, Influence of anatomy and head
position on intranasal drug deposition, Eur. Arch. Otorhinolaryngol. 263 (2006)
827–832.
[283] M.T. Vidgren, H. Kublik, Nasal delivery systems and their effect on deposition and
absorption, Adv. Drug Deliv. Rev. 29 (1998) 157–177.
[284] B. Marple, P. Roland, M. Benninger, Safety review of benzalkonium chloride used
as a preservative in intranasal solutions: an overview of conflicting data and
opinions, Otolaryngol. Head Neck Surg. 130 (2004) 131–141.
[285] A. Rapoport, P. Winner, Nasal delivery of antimigraine drugs: clinical rationale
and evidence base, Headache 46 (2006) S192–201.
[286] C.S. Hankin, L. Cox, D. Lang, A. Bronstone, Z. Wang, M.S. Lepore, P.O. Buck,
Medical costs and adherence in patients receiving aqueous versus pressurized
aerosol formulations of intranasal corticosteroids, Allergy Asthma Proc. 33 (2012)
258–264.
[287] K. Heslop, How to use pressurised metered dose inhalers, Nurs Times, 104 47
(2008) 78–80.
[288] E.A. Gross, J.A. Swenberg, S. Fields, J.A. Popp, Comparative morphometry of the
nasal cavity in rats and mice, J. Anat. 135 (1982) 83–88.
[289] E.E. Morrison, R.M. Costanzo, Morphology of the human olfactory epithelium, J.
Comp. Neurol. 297 (1990) 1–13.
[290] J.D. Hoekman, R.J. HO, Enhanced analgesic responses after preferential delivery
of morphine and fentanyl to the olfactory epithelium in rats, Anesth. Analg. 113
(2011) 641–651.
[291] V. Brown, F. Liu, Intranasal delivery of a peptide with antidepressant-like effect,
Neuropsychopharmacology 39 (2014) 2131–2141.
[292] J.D. Hoekman, R.J. HO, Effects of localized hydrophilic mannitol and hydrophobic
nelfinavir administration targeted to olfactory epithelium on brain distribution,
AAPS Pharm. Sci. Tech. 12 (2011) 534–543.
[293] J.D. Hoekman, M. Hite, A. Brunelle, J. Relethford, R.J. HO, Nasal drug Delivery
Device, WOO2012119153 A2, (2012).
[294] J.D. Suman, B.L. Laube, R. Dalby, Comparison of nasal deposition and clearance of
aerosol generated by nebulizer and an aqueous spray pump, Pharm. Res. 16
(1999) 1648–1652.
[295] W. Moller, G.K. Saba, K. Haussinger, S. Becker, M. Keller, U. Schuschnig, Nasally
inhaled pulsating aerosols: lung, sinus and nose deposition, Rhinology 49 (2011)
286–291.
[296] T.C. Chen, C.D. Fonseca, A.H. Schönthal, Perillyl alcohol and its drug-conjugated
derivatives as potential novel methods of treating brain metastases, Int. J. Mol. Sci.
17 (2016) 1463.
[297] B. Laul, Devices for aerosol delivery to treat sinusitis, J. Aerosol. Med. 20 (2007)
S5–S17.
[298] M. Giroux, Controlled Particle Dispersion. Effective Nasal Delivery from a
Versatile, Flexible delivery Platform, On Drug Delivery Ltd, East Sussex, UK, 2005,
pp. 13–15.
[299] S. Craft, L.D. Baker, T.J. Montine, S. Minoshima, G.S. Watson, A. Claxton,
M. Arbuckle, M. Callaghan, E. Tsai, S.R. Plymate, P.S. Green, J. Leverenz, D. Cross,
B. Gerton, Intranasal insulin therapy for Alzheimer disease and amnestic mild
cognitive impairment: a pilot clinical trial, Arch. Neurol. 69 (2012) 29–38.
[300] P.G. Djupesland, Intranasal insulin improves cognition and modulates beta-amy-
loid in early AD, Neurology 70 (2008) 440–448.
[301] C.C. Wolf, Nosy neuroprotection: intranasal administration of neuroprotective
agents to the brain, Cryonics Magazine, 28 18–20.
[302] X. Jinxiang, W. Zhaoxuan, N. Danielle, W. Thomas, Z. Yue, Nasal and olfactory
deposition with normal and bidirectional intranasal delivery techniques: in vitro
tests and numerical simulations, J. Aerosol. Med. Pulm. Drug Deliv. (2016).
[303] M. Stützle, S. Carle, L. Engelhardt, U. Simon, A. Schafmeister, C. Mavoungou,
K. Schindowski, Protein aerosol for intranasal nose to brain (N2B) delivery, BMC
Proc. 9 (2015) O11.
[304] J.D. Hoekman, M. Hite, A. Brunelle, J. Relethford, R.J. HO, Nasal Drug Delivery
Device, US 20140014104, (2014).
[305] J.D. Hoekman, M. Hite, A. Brunelle, J. Relethford, R.J. HO, Nasal Drug Delivery
Device, CN103917265 A, (2014).
[306] Q. Mingxin, H.E. Renyang, S.H.I. Junwei, Brain-Targeted Nasal Drug Delivery
Device and Body Position Fixator Thereof", WIPO Patent WO/2015/127857.
[307] D. Mittal, A. Ali, S. Md, S. Baboota, J.K. Sahni, J. Ali, Insights into direct nose to
brain delivery: current status and future perspective, Drug Deliv. 21 (2014) 75–86.