1 s2.0 S0169409X14000246 Main PDF

Delivery of antibiotics with polymeric particles
Meng-Hua Xiong
b
, Yan Bao
a
, Xian-Zhu Yang
a
, Yan-Hua Zhu
a
, Jun Wang
a,c,
a
Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
b
CAS Key Laboratory of Soft Matter Chemistry, Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China
c
High Magnetic Field Laboratory of CAS, University of Science and Technology of China, Hefei, Anhui 230026, China
a b s t r a c t a r t i c l e i n f o
Article history:
Accepted 7 February 2014
Available online xxxx
Keywords:
Polymeric particle
Antibiotic
Drug resistance
Bacterial infection
Despite the wide use of antibiotics, bacterial infection is still one of the leading causes of hospitalization and mor-
tality. The clinical failure of antibiotic therapy is linked with low bioavailability, poor penetration to bacterial in-
fection sites, and the side effects of antibiotics, as well as the antibiotic resistance properties of bacteria.
Antibiotics encapsulated in nanoparticles or microparticles made up of a biodegradable polymer have shown
great potential in replacing the administration of antibiotics in their free form. Polymeric particles provide pro-
tection to antibiotics against environmental deactivation and alter antibiotic pharmacokinetics and
biodistribution. Polymeric particles can overcome tissue and cellular barriers and deliver antibiotics into very
dense tissues and inaccessible target cells. Polymeric particles can be modied to target or respond to particular
tissues, cells, and even bacteria, and thereby facilitate the selective concentration or release of the antibiotic at
infection sites, respectively. Thus, the delivery of antibiotics with polymeric particles augments the level of the
bioactive drug at the site of infection while reducing the dosage and the dosing frequency. The end results are
improved therapeutic effects as well as decreased pill burden and drug side effects in patients. The main objec-
tive of this reviewis to analyze recent advances and current perspectives in the use of polymeric antibiotic deliv-
ery systems in the treatment of bacterial infection.
2014 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Problems with antibiotic treatment of bacterial infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.1. The low bioavailability and side effects of antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.2. Intracellular infections that cause resistance to antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. The antibiotic resistance of bacteria in a biolm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.4. The widespread of antibiotic resistant bacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Polymeric particles in antibiotic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Improved pharmacokinetics and biodistribution of antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Overcoming tissue barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.1. Ocular antibiotic delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.2. Gastrointestinal antibiotic delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.3. Pulmonary antibiotics delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3. Enhanced activity against intracellular pathogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3.1. Mycobacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3.2. Brucellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3.3. Salmonellosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.3.4. S. aureus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.4. Biolm infection-related drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Advanced Drug Delivery Reviews xxx (2014) xxxxxx
This review is part of the Advanced Drug Delivery Reviews theme issue on Emergence of multidrug resistance bacteria: Important role of macromolecules as a new drug targeting
microbial membranes.
Corresponding author.
E-mail address: jwang699@ustc.edu.cn (J. Wang).
ADR-12576; No of Pages 14
http://dx.doi.org/10.1016/j.addr.2014.02.002
0169-409X/ 2014 Elsevier B.V. All rights reserved.
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews
j our nal homepage: www. el sevi er . com/ l ocat e/ addr
Please cite this article as: M.-H. Xiong, et al., Delivery of antibiotics with polymeric particles, Adv. Drug Deliv. Rev. (2014), http://dx.doi.org/
10.1016/j.addr.2014.02.002
3.5. Infection-activated delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Discussion and future aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1. Introduction
Bacteria are among the most numerous forms of life on earth. Bacte-
rial infections occur when harmful forms of bacteria successfully invade
the host and begin to reproduce. Bacterial infectious diseases are conta-
gious and include a variety of infections in numerous ecological niches
within the host, ranging from cutaneous infections to deep-seated life-
threatening infections such as pneumonia, endocarditis, septicemia,
osteomyelitis, and other metastatic complications [13]. When the
body is unable to clear the organismafter the initial infection, persistent
infections occur and are accompanied with occasional recurrent re-
lapses of active infection.
Antibiotics are the usual treatment for bacterial infection. Antibiotics
are compounds that either stop bacteria from growing or kill themout-
right, depending on their ability to block critical bacterial cellular pro-
cesses. Most antibiotics can be categorized according to their principal
mechanism of action: (1) agents that interfere with cell wall synthesis,
which include -lactams and glycopeptides; (2) agents that inhibit
protein synthesis, which include macrolides, aminoglycosides, tetracy-
clines, and oxazolidinones; (3) agents that interfere with nucleic
acid synthesis, which include uoroquinolones and rifampin (RIF);
(4) agents that inhibit a metabolic pathway, which include sulfon-
amides and folic acid analogs; and (5) agents that disrupt the bacterial
membrane structure, which include polymyxins and daptomycin [4].
The introduction of antibiotics in the medical eld was one of the
most important interventions to reduce illness; this advance has saved
countless human and animal lives and enabled the development of
modern medical procedures [5]. As a result, antibiotics are the economic
powerhouses of our society; in the USA, there were roughly 42 billion
US dollars worth of sales of antibiotics in 2009, which includes
1530% of drug expenditure among all therapeutic groups of drugs
[5,6]. However, bacterial infectious disease is still responsible for consid-
erable global mortality despite antibiotic treatment [5,7].
2. Problems with antibiotic treatment of bacterial infection
Since the discovery and clinical application of antibiotics, problems
have been revealed in the antibiotic treatment of bacterial infections.
The clinical treatment failure of bacterial infectious disease is associated
with the low bioavailability of antibiotics, the side effects of antibiotics,
tissue and cellular barriers, biolm-related infection and the emergence
of resistant bacteria.
2.1. The low bioavailability and side effects of antibiotics
After drug administration through traditional methods, the drug
reaches a high level in the plasma within hours, but is then rapidly me-
tabolized and excreted from the body before it can reach its target site
[8]. The destruction or inactivation of drugs, especially proteins and
peptides, limits their usage in antibiotic therapy in spite of their proven
efcacy against pathogens in vitro. On the other hand, the systemic ad-
ministration of antibiotics always results in the uniform distribution of
antibiotics throughout the entire body, with only a small fraction
reaching the site of infection, especially in the poorly irrigated areas,
such as ocular and bone structures [9]. Also, bacteria may be protected
by various biological structures around infection foci, such as granulo-
mas and the mucus barrier in the lung, gastrointestinal tract, vagina,
and eye, which increase resistance to antibacterial agents [1012]. For
successful antibiotic therapy, a threshold drug concentration is required
at infected sites for a sufcient period of time. As free antibiotics have a
rapid and short-acting effect, several doses per day are required for
sustained therapeutic concentrations at specic locations. Moreover,
limited drug bioavailability means that drug dosages must be increased
for therapeutic effects, leading to increased side effects.
The side effects of antibiotics are very common. The cellular targets
of antibiotics are often highly genetically and structurally conserved
across diverse members of the bacterial kingdom. Antibiotic treatment
to prevent or eradicate a pathogenic infection is quite likely to induce
concomitant damage to the commensal microbes of the human body,
which can lead to both transient and persistent changes in host health
and physiology, including dietary and nutritional processing, preven-
tion of pathogen invasion, and immune system maturation [13]. The
most common side effects for all types of antibiotics also include gastro-
intestinal side effects, manifested as vomiting, abdominal pain, diarrhea,
and decreased appetite, in addition to allergic reactions. There are side
effects that are specic to each class of antibiotic, such as hepatotoxicity
and other side effects of antituberculosis drugs, nephrotoxicity induced
by aminoglycosides and various side effects of other antibiotic classes
(classied in Table 1). Antibiotic side effects limit the dosing, efciency,
and utility of antibiotics, especially in patients with impaired body
condition.
2.2. Intracellular infections that cause resistance to antibiotics
Phagocytes are crucial in ghting bacterial infections and protect the
body by ingesting (phagocytosing) and destroying bacteria [14]. The be-
havior of bacteria in phagocytic cells is of great importance, as killing
bacteria could terminate the infection. However, bacteria use various
mechanisms to ght for their intracellular survival: they can inhibit
the fusion of lysosomes with phagosomes to form the phagolysosome
[15,16], they can escape from the phagosome into the cytoplasm [17],
or they can resist the microbicidal mechanisms in the phagolysosome
and live inside this structure (Fig. 1A) [18,19]. As a result, pathogens
can survive and even multiply inside different intracellular compart-
ments of phagocytes, including the phagosome, cytosol and
phagolysosome, and continue to evade the immune system [14,20].
While intracellular bacteria are found most often in professional phago-
cytes, including neutrophils, monocytes, macrophages, dendritic cells,
and mast cells, they also nd their way into non-professional phago-
cytes, such as epithelial cells, hepatocytes, and broblasts [19].
Intracellular infections can be produced by various bacteria, includ-
ing obligate intracellular bacteria and facultative intracellular bacteria
[14]. Obligate intracellular bacteria, including Mycobacterium leprae,
Rickettsiae and Coxiella, are host cell-dependent and cannot reproduce
outside their host cells [21]. In contrast, facultative intracellular bacteria
can live or amplify either inside or outside cells and include Mycobacte-
rium tuberculosis, Brucella spp., Salmonella spp., Legionella pneumophila,
Listeria monocytogenes, and Neisseria gonorrhoeae.
For the optimal activity of a givenantibiotic against intracellular bac-
teria, a sufcient concentration of the active drug has to be maintained
in the infected compartments of the cells; this is determined by many
selection criteria, including intracellular penetration, retention, subcel-
lular distribution, and the activity of the antibiotic (Fig. 1B) [19]. Antibi-
otics vary greatly regarding their ability to penetrate cells, as some, like
macrolides, are efciently taken up by cells and others, like aminoglyco-
sides and vancomycin, are not [14]. The rapid uptake of antibiotics into
2 M.-H. Xiong et al. / Advanced Drug Delivery Reviews xxx (2014) xxxxxx
10.1016/j.addr.2014.02.002
cells does not imply that intracellular accumulation occurs. Antibiotics
such as the -lactams have been reported to lack intracellular accumu-
lation because of poor retention in cells despite their rapid cell penetra-
tion [22]. Also, antibiotics could be impaired in the intracellular
environment and become inefcacious against intracellular bacteria
[14,23]. As an example, aminoglycosides with a basic character localize
largely within lysosomes where they are severely impaired due to the
acidic environment [22,24]. Additionally, the subcellular localization of
antibiotics and bacteria may segregate in discrete intracellular compart-
ments [25]. The difculty of clarithromycin to access the phagosome,
where the bacterium frequently resides, limits its efcacy against
mycobacteria in human macrophages [26].
The need for effective intracellular bacterial infection treatments has
been recognized for many years and remains a medical challenge. The
intracellular location of bacteria shields themnot only fromthe host im-
mune response but also fromthe killing effects of many antibiotics [14].
Table 1
Classication, examples and common side effects of each type of antibiotic.
Antibiotics classication Examples of each type Common side effects
Penicillins Penicillin and amoxicillin Gastrointestinal side effects, allergic reactions, hepatotoxicity
Cephalosporins Cephalexin Gastrointestinal side effects, allergic reactions
Macrolides Erythromycin, clarithromycin, azithromycin Gastrointestinal side effects, temporary auditory impairment, cause severe phlebitis
Fluoroquinolones Ciprooxacin, levooxacin, ooxacin Gastrointestinal side effects, central nervous system toxicity, phototoxicity, cardiotoxicity,
arthropathy, and tendon toxicity
Sulfonamides Co-trimoxazole, trimethoprim Allergic reaction
Tetracyclines Tetracycline, doxycycline Gastrointestinal side effects, kidney damage, cramps, skin photosensitivity
Aminoglycosides Gentamicin, tobramycin Ototoxicity, nephrotoxicity
Fig. 1. (A), Bacteria use various ways to ght for their intracellular survival: (1) they can escape from the phagosome to the cytosol; (2) they can resist the microbiocidal mechanisms in
phagolysosome and live inside of the phagolysosome; (3) they can inhibit the fusion of the lysosomes with the phagosomes to formthe phagolysosome. (B), The reasons of the inefcient
antibacterial treatment of antibiotics for intracellular infections: (1) some antibiotics are difcult to penetrate into cells and can only be taken through the process of pinocytosis; (2) the
rapid uptake of some antibiotics is accompanied with their fast efux either through diffusion or efux pumps; (3) antibiotics could be inactivated by the metabolism in cytosol, or the
acidic environment or enzymes in lysosomes; (4) the subcellular localization of antibiotics and bacteria may segregate in diverse intracellular compartments. Take as an example,
when bacteria are in phagolysosomes, antibiotics are accumulated in cytosol.
10.1016/j.addr.2014.02.002
As a reservoir for pathogenic agents, intracellular bacteria are released
from time to time and could disseminate to other tissues, leading to
chronic disease and the recurrence of systemic infections [20].
2.3. The antibiotic resistance of bacteria in a biolm
Bacteria do not live as pure cultures of dispersed single cells. For
quite a long time, it has been known that bacteria adhere to an inert
or living surface and are enclosed in a self-produced hydrated polymer-
ic matrix that forms a biolm structure, within which the bacteria de-
velop into organized communities with functional heterogeneity [27].
The biolm matrix is mainly composed of polysaccharides, proteins,
nucleic acids, and lipids; they cooperate to form a cohesive, three-
dimensional polymer network that interconnects biolm cells and pro-
vides mechanical stability. These qualities make biolms the most suc-
cessful form of life on earth [28]. Bacteria present within biolms
exhibit social behavior analogous to that found in higher organisms in
that they can communicate and rapidly adapt to changing environmen-
tal conditions [29,30].
Biolmformation is common throughout the bacterial lineage and is
one of the important virulence factors of bacteria [31,32]. Biolminfec-
tions occur commonly on medical devices and fragments of dead tissues
such as sequestra of dead bone, and also on living tissues, as in the case
of endocarditis and cystic brosis [27]. Biolmformation on medical de-
vices is an important consideration in terms of infectious disease in the
hospital environment [33]. Biolm infections can be only rarely
defended against by host defense mechanisms and may cause immune
complex damage to surrounding tissues [27]. Biolms act as niduses
of acute infection with planktonic bacterial cells released at any time
until the sessile population is surgically removed from the body [34].
Not only does the biolm matrix provide a structural and protective
physical barrier against harsh environmental conditions such as the
host immune response, desiccation, oxidizing or charged biocides,
metallic cations, and ultraviolet radiation [28,35,36], but it also provides
a physiological niche in whichthe cells become 101000 times more re-
sistant to the killing effects of antibacterial agents [37,38]. Biolms
evade the killing effect of antibiotics by multiple mechanisms (Fig. 2),
which are not fully understood. The matrix of a biolm retards antibi-
otics from penetrating the full depth of the biolm, thus preventing
the access of antibiotics to bacterial cells [27]. Spatial heterogeneity in
the physiological state of bacteria within a biolm leads to the result
that at least some cells can survive any metabolically directed attack
[27]. In a biolm, at least some of the cells adopt a distinct and protected
biolmphenotype, exhibiting slower growth, expression of multi-drug-
resistant efux pumps, expression and/or increased local concentra-
tions of antibiotic-modifying or -degrading enzymes, or alterations in
antibiotic targets [39]. Indeed, surgical intervention is often required
for biolm-related infections to remove infected tissues and/or im-
planted devices, followed by long-lasting chemotherapy and implanta-
tion of a new system, due to the limitation of antibiotic treatment in
biolm-related infections [40,41]. The formation of these sessile com-
munities and their inherent resistance to antibiotics and host immune
attack are at the root of many persistent and chronic bacterial infections
[27].
2.4. The widespread of antibiotic resistant bacteria
The widespread use of antibiotics, in medicine and beyond, has led
to the annual worldwide production of 100,000 to 200,000 tons of
these compounds [42]. This has imposed evolutionary pressure, pro-
moting the development of antibiotic resistance in bacteria, which are
able to survive exposure to one or several antibiotics. The continuous
evolution of antibiotic resistant bacterial strains stresses the limitations
of current antibiotics. The failure of conventional treatment always re-
sults in treatment with second- or third-choice antibiotics that are less
effective, more toxic, or more expensive and ends up with a greater
risk of death [43]. In some cases, bacteria have become so resistant
that no available antibiotics are effective against them. Genes that
Fig. 2. Mechanisms that biolms evade the killing effect of antibiotics. The matrix of a biolmretard antibiotics from penetrating the full depth of the biolm, thus reducing access of the
antibiotcs to the cells. The antibiotic-inactivating enzymes produced by bacteria are concentrated in biolm and inactivate antibiotics before they can reach their target sites. Spatial
heterogeneity in the physiological state of bacteria (as indicated with different colors of bacteria) within biolm leads to the result that at least some of the cells could survive any met-
abolically directed attack. Some bacteria express multi-drug-resistant efux pumps that can exclude antibiotic out of the cells. Biolms act as niduses of acute infection with planktonic
bacterial cells released at any one time. (For interpretation of the references to color in this gure legend, the reader is referred to the web version of this article.)
10.1016/j.addr.2014.02.002
confer antibiotic resistance canbe a result not only of spontaneous or in-
duced genetic mutation, but also of horizontal gene transfer between
bacteria, which leads to the spread of resistance between bacterial spe-
cies. Currently, antibiotic resistance occurs everywhere in the world.
About 440,000 new cases of multidrug-resistant tuberculosis (MDR-
TB) emerge annually, causing at least 150,000 deaths [44]. In the
European Union, 25,000 people die each year as a result of infection
with multidrug resistant bacteria, at anestimated cost to healthcare sys-
tems of 1.5 billion per year [45]. In the US, it is reported that between
50 and 60% of all hospital-acquired infections are caused by antibiotic
resistant bacteria [46], and the total cost to American society attributed
to drug resistant infections is estimated at more than $35 billion a year
[45]. Despite the increasing need for newantibiotic therapies, the num-
ber of newly approved drugs continues to decline. Antibiotic resistance
therefore poses a signicant problem. The World Health Organization
(WHO) selected combating antimicrobial resistance as the theme for
World Health Day 2011.
The mechanisms behind antibiotic resistance can be arranged into
four main categories. First, bacteria may encode enzymes that inactivate
or modify antibiotics before they canhave aneffect, suchas deactivation
of penicillin G through -lactamases. Second, bacteria may alter the tar-
get sites of antibiotics by modifying or eliminating binding sites, such as
a change in penicillin-binding protein 2B that results in penicillin resis-
tance. Third, bacteria may alter a metabolic pathway. Fourth, bacteria
may reduce drug accumulation in cells by expressing efux systems
that pump antibiotics out of cells before the drugs can reach their target
sites and exert their antibacterial effects; alternatively, bacteria may
down-regulate or change the outer membrane channels required for
the cell entry of drugs.
3. Polymeric particles in antibiotic therapy
In the last few decades, a great number of studies have focused on
developing novel and efcient drug delivery systems to meet different
clinical needs [4750]. Polymeric particles, including nanoparticles
and microparticles made of natural and synthetic polymers, have
shown several advantages as drug carriers, such as high stability both
in vitro and in vivo, good biocompatibility, and multifunctionality
[51,52]. This potential has been explored for encapsulating antibiotics
in polymeric particles, which allows slow, sustained release of the
drug, improves the pharmacokinetics and biodistribution of antibiotics,
overcomes cellular and tissue barriers, and improves antibacterial ef-
cacy against biolm-related infectious disease [8,14].
3.1. Improved pharmacokinetics and biodistribution of antibiotics
Polymeric particles have the ability to solve the technical problems
of solubility and to alter the pharmacokinetics of sparingly soluble or
hydrophobic antibiotics, which is associated with several serious prob-
lems, such as poor absorption upon oral administration and drug aggre-
gationafter intravenous administrationwhichmight cause local toxicity
and reduce systemic bioavailability. Since almost one half of potentially
valuable drug candidates identied by high-throughput screening tech-
nologies are abandoned due to the poor solubility in water, this techni-
cal advance may provide more drug candidates for clinical practice.
Polymeric particles also provide a protective coat for bioactive antibi-
otics against environmental degradation and deactivation and protect
themfromthe body's clearing mechanisms, so that sustained therapeu-
tic concentrations can be maintained in the body.
There is considerable evidence of the benets of polymeric particles
as antibiotic delivery systems. Administration of encapsulated particles
containing antibiotics alters the tissue distribution and plasma pharma-
cokinetics of the drug and increases the concentration of antibiotics at
the site of infection, thus increasing drug bioavailability. For infectious
diseases that occur in mononuclear phagocyte system (MPS) tissues,
particularly in the liver and spleen, polymeric particles are expected to
be rapidly recognized and withdrawn from the circulation by the
phagocytic cells of the reticuloendothelial system(RES), where bacteria
are often located, to reach high drug concentrations at the infection site
[14,23]. Poly(lactide-co-glycolide) (PLGA) particles as carriers for anti-
biotics could successfully deliver drugs to MPS tissues for the treatment
of infectious disease caused by intracellular pathogens in the liver and
spleen [53]. However, prolonged circulation of particles is needed to
maintain the required therapeutic level of antibiotics in the blood for
extended time periods in infectious diseases not restricted to MPS tis-
sues. Long-circulating particles can slowly accumulate at infection
sites due to the leaky vasculature [54].
The concept of slow and sustained release from a biodegradable
polymeric particle is a crucial aspect of drug delivery, as maintaining
the proper drug concentrationfor a relatively long time reduces the dos-
ing frequency andthe dosage, while administration of the free antibiotic
exhibits a quick and short effect and requires several doses per day.
3.2. Overcoming tissue barriers
The treatment of bacterial infectious diseases by antibiotics is usually
complicated by the rapid clearance of antibiotics from organs, the envi-
ronmental deactivation of the drug and the barriers of tissues, such as
the mucosal barriers of the ocular, gastrointestinal, and respiratory tis-
sues [1012]. Polymeric particles are able to protect the drug against
degradation and the body's clearing mechanisms as well as facilitate
transport across critical and specic barriers (Fig. 3).
3.2.1. Ocular antibiotic delivery
A major problem in ocular therapeutics is the low bioavailability of
drugs caused by blinking, tear turn-over, instilled uid drainage, tear
evaporation, and systemic absorption, with typically less than 5% pene-
tration of the drug applied to the cornea into intraocular tissues [55,56].
In order to achieve a therapeutic effect, frequent administrationof drugs
is necessary; however this is frequently associated with undesirable
side effects caused by systemic drug absorption [57]. Moreover, therapy
with systemic administration of drugs requires large doses due to the
strong bloodocular tissue barrier. The formulation of biodegradable
polymer particles as drug delivery systems holds signicant promise
for ophthalmic drug delivery, which can provide sustained drug release,
reside on the surface of the eye for a prolonged period, and penetrate
through the cornea. Different strategies have been developed to
increase drug bioavailability by prolonging the contact time of the
formulation with the corneal/conjunctival epithelium. Drug delivery
systems based on synthetic and natural polymers such as PLGA
[5863], poly(lactide) (PLA) [64], poly (-caprolactone) (PCL) [65,66],
poly(isobutylcyanoacrylate) [6769], albumin [70], and chitosan (CS)
[7173] have shown great potential in improving ocular drug delivery
in various cell culture and animal models.
To optimize delivery systems for ocular drug delivery, the effects of
particle size and surface properties were investigated [74]. Uptake of
PLGA particles in rabbit conjunctival epithelial cells was found to be
dependent on the particle size. Smaller (100 nm) particles exhibited
the highest uptake compared to larger (800 nmand 1000 nm) particles;
moreover, 100 nm particles were able to penetrate across the corneal
barrier.
The surface properties of particles also have a great effect on the
efciency of delivery systems. The effect of pegylation on the ability of
PLA nanospheres to increase the corneal penetration of acyclovir and
thereby to improve the ocular bioavailability of the drug was investigat-
ed in vivo in male New Zealand rabbits [64]. The aqueous AUC
0 6
values were signicantly (p b 0.001) greater for poly(ethylene glycol)
(PEG)-coated PLA nanospheres than for uncoated nanospheres and
the free drug suspension with a 1.8-fold and 12.6-fold increase, respec-
tively. The increase in acyclovir bioavailability provided by PEG-coated
PLA nanospheres could have been caused by improved mucoadhesion
enhanced by PEG. A similar conclusion was also made by Young et al.
10.1016/j.addr.2014.02.002
in that PLGA microparticles with PEG adhere better to the mucous
membrane compared to microparticles without PEG [75]. Angela et al.
prepared PCL nanocapsules, CS-coated PCL nanocapsules and PEG-
coated PCL nanocapsules to study the inuence of the surface character-
istics of colloidal drug carriers in their interaction with different biolog-
ical surfaces [76]. The results suggest that the PEG coating accelerates
the transport of nanocapsules across the epithelium, whereas the CS
coating favors the retention of nanocapsules in the supercial layers of
the epithelium. The specic behavior of CS-coated systems was also
corroborated in vivo.
There is growing evidence that mucoadhesive polymers can be used
to enhance the transport of usually poorly absorbed, hydrophilic drugs
across epithelial diffusion barriers. A mucoadhesive carrier system
would be a promising step towards the treatment of external ocular dis-
eases by using mucoadhesive polymers, which may interact intimately
with these extraocular structures, avoid particle clearance, prolong the
residential time of the formulation at the administration site, and retain
the drug at the absorption site [75,77].
Among the wide variety of mucoadhesive polymers, the cationic
polymer CS has been used because of its unique properties, including
acceptable biodegradability and biocompatibility. CS nanoparticles
have been developed for ocular drug delivery. In vivo studies have
shown that the amount of CS nanoparticles in the cornea and conjunc-
tiva is signicantly higher than that of a control solution; these levels
were fairly consistent for up to 24 h, and the nanoparticles were
observed to penetrate into the corneal and conjunctival epithelia [72].
Further in vivo studies have also shown that CS nanoparticles are well-
tolerated by ocular surface structures [72]. CS-sodium alginate (ALG)
nanoparticles have also been investigated as a vehicle for the prolonged
topical ophthalmic delivery of gatioxacin [71]. Microparticles based on
quaternary ammonium chitosan derivatives have shown similar or
often better properties than formulations made of chitosan with respect
to size, in vitro release behavior, and mucoadhesiveness, making them
more suitable for ocular administration. Additionally, these prepara-
tions do not show any cytotoxic effects in vitro and can therefore be
considered a safe carrier [73].
Other mucoadhesive polymers that adhere to mucinepithelial sur-
faces have recently gainedattentioninocular drug delivery. Microspheres
fabricated by a spray drying method using a mixture of bioadhesive poly-
mers such as pectin, polycarbophil, and hydroxypropylmethyl cellulose
(HPMC) have been developed as a carrier of sulfacetamide sodium (SA)
for the treatment of ocular keratitis [78]. The SA-loaded polycarbophil
microsphere formulation completely eradicated the bacteria from the
eye after six days of treatment, while the SA suspension alone was
found to be not clinically effective in the treatment of bacterial keratitis
induced by Staphylococcus aureus and Pseudomonas aeruginosa. As
another example, gatioxacin/prednisolone loaded nanoparticles were
prepared using Eudragit RS 100 and RL 100 (copolymers of poly(ethyl
acrylate), methyl methacrylate and chlorotrimethyl-ammonioethyl
methacrylate) and coated with a bioadhesive polymer, hyaluronic acid
[77]. The nanoparticle suspensions revealed signicantly prolonged
drug release compared to the free drugs with no burst effect. The maxi-
mum corneal concentration after treatment with nanoparticles was
5.23-fold higher than that achieved with commercial eye drops. In addi-
tion, the effect of the commercial eye drops had almost disappeared
after 2 h, while that of the HA coated nanoparticles lasted for more than
6 h. Similarly, the nanoparticles showed a 1.76-fold increase in the C
max
of gatioxacin in the aqueous humor in comparison to the eye drops.
The resulting nanoparticle suspension is promising for reducing dose
frequency and improving patient compliance.
3.2.2. Gastrointestinal antibiotic delivery
Helicobacter pylori, the main etiological factor in the development of
gastritis, gastric ulcers, and gastric carcinoma, resides mainly in the gas-
tric mucosa or at the interface between the mucous layer and the epi-
thelial cells of the antral region of the stomach [7981]. Although
H. pylori is sensitive to most antibacterial agents in culture, single anti-
biotic therapy is not effective for the eradication of H. pylori infection
in vivo due to the lowconcentration of the antibiotic reaching the bacte-
ria under the mucosa, the instability of the drug in low pH gastric uid,
and the short residence time of the antibiotic in the stomach [82]. To
completely eradicate H. pylori, a combination of more than one antibiot-
ic and an anti-secretory agent is required; however, combination thera-
py is limited due to the side effects and the cost of therapy. In recent
years, polymeric drug delivery systems, especially mucoadhesive poly-
meric systems for sustained delivery of antibiotics in the gastric mucosa,
are regarded as good strategies to improve the eradication efcacy of
H. pylori [8387]. The development of polymeric nanoparticles for oral
drug delivery to overcome gastrointestinal mucosal barriers has been
reviewed recently [12].
3.2.3. Pulmonary antibiotics delivery
Therapies targeting respiratory tract infections represent the largest
proportion of the antibacterial market [88]. In the last decade, the deliv-
ery of antibiotics to the lung through inhalation has gained increasing
attention for the treatment of pulmonary infections, offering the
Fig. 3. Mechanisms of polymeric particles as a carrier of antibiotics to overcome tissue barriers. Antibiotic treatment is usually complicated by the rapid clearance of antibiotics fromorgans,
the inactive of the drug and the barriers of tissues. Polymeric particles are able to protect the drug against degradation and the body's clearing mechanisms as well as facilitate transport
across critical and specic barriers, thus drugs are sustained released to maintain a proper drug concentration for a relatively long time.
10.1016/j.addr.2014.02.002
attractive advantages of delivering high drug concentrations directly to
the site of infection, reducing toxicity, and improving the therapeutic
potential of existing antimicrobial agents [89]. The major challenges
faced by localized treatment of respiratory tract infections are the
rapid absorption and clearance of antibiotics from the lungs and the
inability to consistently access the deep lung, where the site of infection
usually lies. Polymeric nanoparticles and microparticles have been
shown to have the potential to provide controlled drug delivery to
the lung, with sustained release of drugs in the lung so as to prolong
drug action, reduce side effects, and improve patient compliance
[90,91]. Particularly, PLGA microparticles have received much atten-
tion as a carrier of antibiotics for pulmonary delivery [9295]. To suc-
cessfully target specic areas of the lungs, the particle size must be
carefully controlled. Researchers have found that particles of about
13 m in diameter deposit with high efciency to the deep lung
and particles of about 48 m in diameter deposit in the bronchial
region; larger particles (N10 m) tend to be deposited along the
oropharyngeal cavity [96].
PLGA nanoparticles have also been reported as useful pulmonary
drug delivery carriers for improving the pharmacological effect of a
drug [97]. After intratracheal instillation of FITC encapsulated PLGA
nanospheres to a rat, FITC was found in the rat's lungs, liver, kidney,
brain, spleen, and pancreas, as demonstrated by immuno-histo-
chemical staining with a dye. FITC remained in the alveoli for at least
1.5 h after the intratracheal administration of PLGA nanospheres, but
FITC had almost disappeared 24 h later. In another example, Ungaro
et al. developed PLGA NPs embedded in an inert microcarrier made of
lactose, referred to as nano-embedded micro-particles (NEM), for the
production of dry powders for antibiotic inhalation as a pulmonary de-
livery system[97]. Employing helper hydrophilic polymers, such as chi-
tosanand PVA, is essential to optimize the size andmodulate the surface
properties of tobramycin (Tb)-loaded PLGA NPs, whereas the use of Alg
allows efcient Tb entrapment within NPs and its release for up to one
month [97]. In vivo biodistribution studies have shown that PVA-
modied Alg/PLGA NPs reach the deep lung, while CS-modied NPs
are found in great amounts in the upper airways, lining lung epithelial
surfaces [97].
3.3. Enhanced activity against intracellular pathogens
Despite the availability of antibiotics, the treatment of intracellular
infections often completely fails to eradicate the pathogen [14,23]. Poly-
meric delivery systems of antibiotics, including nanoparticles and mi-
croparticles, can be endocytosed by phagocytic cells and then release
drugs into these cells [14]. In the past decade, many advances have
been made in the eld of these delivery systems containing antibiotics
against different intracellular infections. These carrier systems are bio-
degradable and biocompatible and remain stable under in vivo condi-
tions, more so than with liposomes. Several in vivo and in vitro studies
have reported the potential applications of polymeric delivery systems
to increase the selectivity of antibiotics for phagocytic cells and enhance
therapeutic efciency in the treatment of intracellular infections. The
uptake of polymeric particles by the mononuclear phagocyte systemre-
sults in the accumulation of the drug in the liver and spleen, the major
sites of intracellular infection, leading to a decrease in bacterial number
in these tissues.
3.3.1. Mycobacteria
Tuberculosis (TB), caused by M. tuberculosis, is the second most
deadly infectious disease [98,99]. The current treatment of pulmonary
TB involves prolonged oral administration of high systemic doses of
combinedantibiotics, witha cocktail of four front-line drugs: rifampicin
(RFP), isoniazid, pyrazinamide, and ethambutol, given daily for 6
8 months or longer by the oral route, which is associated with unwanted
side effects and poor compliance. In addition, most antibiotics are rela-
tively ineffective for the treatment of intracellular infections of TB.
Novel delivery systems facilitate the selective accumulation of antibiotics
to the site of infection, provide slow and sustained drug release and en-
hance the accumulation and activity of intracellular antibiotics, which al-
lows administrationover longer time intervals [8,98]. PLGAmicrospheres
containing RFP release the drug at an almost constant rate for 20 days
after a lag phase observed for the initial 7 days at pH7.4. Moreover, deliv-
ery of RFP to alveolar macrophages is highly effective, withalmost 19-fold
higher concentration of RFP achieved in alveolar macrophages compared
to administrationof the free drug solution[99]. Oral delivery of antituber-
culous drugs by PLGA microspheres has been found to release drugs in a
sustained manner [100,101]. Pharmacokinetic analyses have revealed
that drug-loaded PLGA microparticles exhibit a higher peak concentra-
tion, a greater area under the concentration time curve, and a delayed
elimination rate [100]. Drug levels above the MIC have been observed
up to 72 hafter administrationinplasma andfor 9 days invarious organs.
Chemotherapy has shownbetter or equivalent clearance of bacteria using
drug-loaded PLGA microparticles (weekly) than with free drugs (daily)
[101]. PLGA nanoparticles have also been reported to signicantly en-
hance the bioavailability of antibiotics, and a combination of econazole
and moxioxacin and RIF in PLGAnanoparticles resulted in total bacterial
clearance from the organs of mice in 8 weeks [102]. Injection of PLGA
nanoparticles and microparticles has also shown promise for increasing
drug bioavailability and reducing dosing frequency for better manage-
ment of tuberculosis [102104].
M. tuberculosis can survive in alveolar macrophages, the rst defense
against lung infection, by preventing phagosome maturation and
phagosomelysosome fusion, thereby avoiding exposure to the lower
pH and hydrolytic environment of the phagolysosome [105,106].
Targeting extended release formulations of the drug to the lungs, the
primary site of infection, is promising for the treatment of TB, which
may then result in a lower systemic dose, reduced frequency of dosing
and shortened treatment times compared to standard oral or systemic
treatment alone to achieve the desired therapeutic effect [98,107,108].
Pharmacokinetic studies using intratracheal insufation of RFP-loaded
PLGA microparticles delivered to guinea pigs have shown signicantly
increased drug levels in the lungs compared to oral or intravenous
delivery of RFP, and thus a better therapeutic benet [109,110]. RFP-
loaded PLGA microspheres signicantly increase drug levels in the
lungs, reduce the number of viable bacteria, and reduce inammation
and lung damage compared with a daily dose of nebulized RFP suspen-
sion in guinea pigs infected with M. tuberculosis [109].
Phagocytosis depends greatly on the particle size and the number of
particles administered. The ideal diameter is between 1 m and 6 m,
but a few 10 m particles are also taken up [111]. It has been found
that the most efcient delivery of antibiotics into a large population of
macrophages is achieved by the phagocytosis of 3 m particles [111].
3.3.2. Brucellosis
Brucellosis remains a major zoonosis worldwide, caused by Brucella
abortus, Brucella melitensis, Brucella suis, and Brucella canis [112]. The
treatment of brucellosis is difcult due to its intracellular survival and
proliferation within phagocytic cells, since most antibiotics, although
highly active in vitro, do not actively pass through cellular membranes
[113]. Treatment for brucellosis remains controversial and requires
prolonged therapy with at least two agents. Relapses are frequent
owing to the low efcacy of many drugs and the lack of patient
compliance.
Biodegradable microspheres made of PLGA and containing gentami-
cin sulfate have been used to target B. abortus-infected J774 monocyte
macrophages in vitro [114]. The microspheres afford controlled release
of gentamicin over 50 days in vitro. Microspheres of PLGA containing
gentamicin show good activity against intracellular brucellosis. The
authors prepared gentamicin-loaded microspheres made of the end-
group capped PLGA 50:50 (esteried end-groups) and the end-group
uncapped PLGA 50:50H (free hydroxyl and carboxyl end-groups) and
found that the end-group uncapped PLGA 50:50H showed better
10.1016/j.addr.2014.02.002
activity against intracellular bacteria (typically by a 2 log10 reduction in
comparison with untreated infected cells) than end-group capped PLGA
50:50 (about a 1 log10 reduction in comparison with untreated infected
cells). The addition of 2% poloxamer 188 to the microsphere dispersion
medium further reduced infection, while opsonization of the particles
with non-immune mouse serum had no effect on the antibacterial ef-
cacy of the microspheres. Placebo PLGA 50:50 and PLGA 50:50Hmicro-
spheres had no bactericidal activity. In another study, these authors
demonstrated that gentamicin-containing PLGA microspheres were
successfully phagocytosed by infected THP-1 human monocytes, and
immunocytochemistry studies revealed that the antibiotic reached
Brucella-specic compartments [115].
Drug delivery systems containing gentamicin have been further
studied as a treatment against experimental brucellosis in mice [53].
PLGA nanoparticles containing gentamicin show selective distribution
in the liver and spleen of mice, with potential applications in the treat-
ment of brucellosis. The values of the pharmacokinetic parameters after
administration of a single intravenous dose of 1.5 mg/kg of body weight
of loadedgentamicinrevealed greater areas under the curve for the liver
and the spleen and increased mean retention times compared to those
for the free drug. The administration of three doses of 1.5 mg/kg signif-
icantly reduced the load associated with splenic B. melitensis infection.
Mohamed et al. also developed polymerantibiotic nanoplexes
using the anionic copolymer PEO-PAA
Na
+
to incorporate streptomy-
cin and doxycycline via cooperative electrostatic interactions between
the cationic drug and anionic polymer [116]. Administration of two
doses of the nanoplexes signicantly reduced the B. melitensis load in
the spleens and livers of infected BALB/c mice. The nanoplexes were
more effective than free drugs in the spleens (0.72-log and 0.51-log
reductions, respectively) and in the livers (0.79-log and 0.42-log reduc-
tions, respectively) of the infected mice.
3.3.3. Salmonellosis
Salmonella infections are zoonotic and many infections are due to
ingestion of contaminated food. Salmonella causes salmonellosis and
typhoid fever and is a facultative intracellular parasite, which makes
treatment more difcult [117,118].
Ampicillin-loaded polyisohexylcyanoacrylate nanoparticles showed
good activity for the treatment of intracellular Salmonella infections
in vitro and in vivo. The nanoparticles signicantly enhanced the intra-
cellular uptake of ampicillin in infected murine macrophages and
found that (
3
H)ampicillin uptake increased 9-fold in the J774 cell line
and 20-fold in peritoneal macrophages [119]. Transmission electron
microscopy showed that nanoparticles were actively endocytosed by
peritoneal macrophages, and nanoparticles were found to be present
either in isolated form or closely associated with bacteria inside
phagosomes or phagolysosomes [120,121]. The intracellular distribu-
tion of (
3
H)ampicillin was then investigated using ultrastructural auto-
radiography, and the results indicated that the delivery of ampicillin by
nanoparticles allowed its penetration into macrophages and vacuoles
infected with Salmonella typhimurium [121]. The nanoparticles were
found to dramatically improve the therapeutic efciency of the drug
in experimental intracellular infections in vivo [122]. All control mice
and all those treated with non-loaded nanoparticles died within
10 days of infection, while all mice treated with a single injection of
0.8 mg of nanoparticle-bound ampicillin survived. However, for free
ampicillin, three doses of 32 mg each per mouse were required to
reach a similar curative effect. This can be explained since, when
bound to nanoparticles, ampicillin was concentrated mainly in the
liver and spleen, the primary foci of infection in the experimental
model that we used. On another study, 0.8 mg of ampicillin bound to
nanoparticles had a greater therapeutic effect than 48 mg of free
ampicillin in S. typhimurium infected mice [123].
Similar results have been obtained using ceftriaxone sodiumloaded
chitosan nanoparticles [124], gentamicin-loaded Pluronic-based core-
shell nanostructures, and gentamicin loaded nanoplexes based on
block copolymers of poly(ethylene oxide-b-sodium acrylate) (PEO-b-
PAA
+
Na) [125] or poly(ethylene oxide-b-sodium methacrylate)
(PEO-b-PMA
+
Na) [126].
3.3.4. S. aureus
S. aureus is a major cause of infectious morbidity and mortality in
community and hospital settings, as about one third of the human pop-
ulationcarries this bacterium[127,128]. S. aureus cause diverse invasive,
life-threatening infections despite the availability of effective antimicro-
bial agents, such as pneumonia, endocarditis, and septicemia [129,130].
Biswas developed biocompatible, encapsulated tetracycline (Tet) in
200 nm-sized O-carboxymethyl chitosan nanoparticles (Tet-OCMC
Nps) via ionic gelation for sustained delivery of Tet into cells [131].
Tet-O-CMC Nps were six-fold more effective in killing intracellular
S. aureus compared to Tet alone in HEK-293 and differentiated THP1
macrophage cells, proving this an efcient nanomedicine to treat intra-
cellular S. aureus infections. PLGA nanoparticles can also provide high
cellular accumulation of antibiotics and effectively kill intracellular
S. aureus [132,133].
3.4. Biolm infection-related drug delivery
A biolmis a sessile community of bacterial cells that is enclosed by
a self-secreted matrix composed of an extracellular polymeric sub-
stance (EPS), which renders the bacteria less susceptible (i.e. 10 to
1000-fold) to antimicrobial agents compared to their planktonic cell
counterparts [134]. The key elements in the infectious process and
formation of a biolm for drug delivery systems are the prevention of
colonization and biolmformation, accumulation at the biolmsurface,
and drug penetration into the biolm [135]. Many studies have been
performed to prevent biolm formation such as the surface modica-
tion of devices to reduce bacterial attachment and biolmdevelopment
as well as the incorporation of antimicrobials to prevent colonization,
which have been reviewed elsewhere [135137].
Chronic biolm infections are present in the lungs of cystic brosis
and chronic obstructive pulmonary disease patients [138140]. Because
of the high tolerance of biolm towards antibiotics, a high therapeutic
dose is needed, which poses a high risk of systemic toxicity using the
conventional antibiotic delivery routes of oral and intravenous adminis-
tration. Delivering the antibiotic directly to the lung by inhalation is
therefore preferred to reduce the risk of systemic toxicity. However,
the inhaled antibiotic is rapidly removed from the lungs, limiting the
amount of time that the drug can remain at a concentration above the
effective minimum inhibitory concentration and requiring at least
twice-a-day administration. Additionally, the presence of a thick
mucus layer surrounding biolm colonies can bind and deactivate
antibiotics, thereby negating the therapeutic effects of inhaled antibi-
otics [141,142]. For aminoglycosides, slow penetration due to electro-
static interactions with the mucus and biolm matrices and the lack of
activity against cells with a slow growth phenotype are particularly
important; moreover, sub-inhibitory levels of aminoglycosides help to
induce biolm formation [143]. The encapsulation of antibiotics into
nanoparticles can overcome the problem of antibiotic deactivation as
it prevents interactions between the antibiotic and sputum contents
and allows the drug to pass through the sputum(with an average spac-
ing in sputummesh of 60300 nm[141]) to reach embedded biolm
colonies [142,144,145]. Moreover, nanoparticles can effectively evade
pulmonary phagocytic clearance, exhibit a longer retention time in the
lung, release drugs in a sustained manner, and increase antibiotic
residence time and concentration at biolm infection sites, which
leads to greater antibacterial efcacy than that obtained with a free-
drug formulation [90,91].
Cheow and colleagues have demonstrated that the release prole is
important for the antibacterial efcacy of antibiotic-loaded nanoparti-
cles [146]. Biolmcells that survive the initial antibiotic exposure exhib-
it a higher antibiotic tolerance than fresh biolm cells; the lower the
10.1016/j.addr.2014.02.002
initial exposure, the higher the tolerance of the surviving biolm cells.
Thus, a successful inhaled antibiotic therapy against biolm infections
requires a biphasic extended release prole, where fast antibiotic re-
lease in the early stage of treatment ensures a high initial antibiotic con-
centration and the slower extended release sustains a sufciently high
antibiotic concentrationto inhibit biolmgrowthand to minimize exac-
erbations. The size of the particles is also important for transport
through the mucus barrier; the most efcient particles have a size of
b300 nm [147].
Liposomes have been used as carriers of antibiotics for the treat-
ment of biolminfection as these materials interact closely with bac-
terial cells through fusion of liposomes with the bacterial cell
membrane [148150]. However, the clinical effectiveness of inhaled
liposomal delivery remains debatable due to potential problems
such as drug leakage as well as poor stability to temperature and
pH uctuations. In this regard, Cheow and colleagues have devel-
oped lipidpolymer hybrid nanoparticles, which are made up of a
polymer nanoparticle core and a lipid coat [151153]. These hybrid
nanoparticles likely possess both liposome and polymeric nanoparti-
cle characteristics, biolm-targeting, and controlled drug release and
thus may be benecial for anti-biolm therapy. Compared to poly-
mer nanoparticles without lipids, these hybrid nanoparticles have
been found to be larger in size due to the lipid coat and equally stable
and exhibit equal or higher drug loading depending on the drug's
lipophilicity. This enables the targeted release of the encapsulated
drug in the vicinity of biolm colonies by responding to the presence
of rhamnolipids, which are ubiquitously present in biolm colonies
of P. aeruginosa. However, more studies are necessary to evaluate
the potential of polymeric particles as carriers of antibiotics for the
treatment of biolm infections.
Bolhuis and colleges have developed a triple-layered electrospun
matrix consisting of a central layer of poly(ethylene-co-vinyl acetate)
(PEVA) sandwiched between outer layers of PCL, which display
sustained antibiotic release in formulations that can stop biolmforma-
tion, kill preformed biolms and kill mature, dense biolm colonies of
S. aureus MRSA252 [154].
3.5. Infection-activated delivery system
Aninteresting approachfor antibiotic delivery has beenthe develop-
ment of systems that differentially deliver therapeutic agents to infec-
tion sites. When bacterial infection happened, bacteria will secrete
many virulence factors, such as phospholipase, phosphotase, lipase,
toxins, protease, acidic pH and so on, to develop unique microenviron-
ments [155]. Strategies utilizing the unique microbial infection environ-
ment as a molecular cue to activate drug release or facilitate their
binding to the bacteria can achieve such an ambitious goal (Fig. 4).
These new strategies can improve antibiotic targeting and activity
with fewer side effects and can overwhelmdrug resistance mechanisms
with high, sustained local drug concentrations.
Zhang and co-workers have reported the rst example of the
selective delivery of antimicrobials to sites of bacterial infection
that respond to bacterial toxins to activate drug release [156].
They developed chitosan-modied gold nanoparticles attached to
the surface of liposomes which effectively prevent undesirable pay-
load release in regular storage or physiological environments.
However, once these protected liposomes sense bacteria that se-
crete toxins, the toxins will insert into the liposome membrane and
form pores, through which the encapsulated therapeutic agents are
released. Considering the tremendous availability of bacterial
toxins at bacterial infection sites and their pore-forming activities,
the strategy allows for the smart release of drugs at infection
sites to kill toxin-secreting bacteria without producing toxic effects
in healthy tissues.
We have developed a lipase-sensitive polymeric triple-layered
nanogel (TLN) for the differential delivery of antimicrobials to bacterial
infection sites [157]. The TLN contains a bacterial lipase-sensitive PCL
interlayer between a cross-linked polyphosphoester core and a shell
of PEG. The PCL molecular fence protects the drug inside the
polyphosphoester core with minimal drug release prior to reaching
sites of bacterial infection, thus eliminating potential adverse side ef-
fects. However, once the TLN senses lipase-secreting bacteria, the PCL
fence of the TLN is degraded by lipase to release the drug. Using
Fig. 4. Schematic representation of a bacterial infection activated polymeric drug delivery system. 1, Drug release from antibiotics-loaded polymeric particles were activated utilizing the
unique microbial infection environment as a molecular cue, suchas phospholipase, phosphotase, lipase, toxins, protease and so on; 2, Antibiotics-loaded polymeric particles were activated
by the surface charge-switching mechanism due to acidic environment of bacterial infection, facilitating their binding to negatively charged bacteria.
10.1016/j.addr.2014.02.002
S. aureus as a model bacteriumand vancomycin as a model antimicrobi-
al, we have demonstrated that the TLN released almost all the encapsu-
lated vancomycin within 24 h, but only in the presence of S. aureus,
signicantly inhibiting bacterial growth. The TLN further delivered the
drug into bacteria-infected cells and efciently released the drug to
kill intracellular bacteria.
Bacterial phosphatase and phospholipase are of paramount impor-
tance for the normal function of metabolic and signaling pathways
and are a key virulence factor of pathogens [158160]. We have devel-
oped a bacterial phosphatase and phospholipase-responsive multifunc-
tional nanogel for targeted antibiotic delivery to macrophages to treat
bacterial infections [161]. This nanogel contains mannosyl ligands
conjugated to the shell of the poly(ethylene glycol) armed and
polyphosphoester core-crosslinked nanogel, which can be degraded
by active phosphatases or phospholipases produced by bacteria to re-
lease the drug. Mannosylation endows the nanogel with the advantages
of potentially targeted antibiotic delivery to macrophages that express
highlevels of the mannose receptor as well as drug accumulationat bac-
terial infectionsites through macrophage transport. At the infection site,
macrophages further ingest bacteria, triggering the degradation of the
drug-containing polyphosphoester core by the active phosphatase or
phospholipase produced by the bacteria and thereby kill the bacteria.
Therefore, this nanogel provides macrophage targeting and lesion site-
activatable drug release properties and also enhances bacterial growth
inhibition.
LowpHis particularly signicant bothbecause of its association with
serious infections and its implications for treatment. Bacteria may in-
habit acidic environments in the body either because acidity is the nat-
urally prevailing condition, suchas the stomach(pH 1.02.0), intestines
(pH 5.08.0), vagina (pH 4.05.0), bladder (pH 4.58.0), and skin
(pH 4.05.5), or through a combination of bacterial activity and the
resulting immune response. Certain antibiotics are known to demon-
strate signicant loss of activity in an acidic environment [162], and
even more troubling, a reduction in localized pH is usually a sequela
of worsening disease severity and prognosis, i.e. precisely when maxi-
mal efcacy is most needed [163]. Farokhzad and coworkers have de-
veloped drug-encapsulated, pH-responsive, surface charge-switching
poly(D,L-lactic-co-glycolic acid)-b-poly(L-histidine)-b-poly(ethylene
glycol) (PLGA-PLH-PEG) nanoparticles for treating bacterial infections
[24]. These nanoparticle drug carriers are designed to shield non-
target interactions at pH 7.4, but bind avidly to bacteria in an acidic
environment, delivering drugs andmitigating inpart the loss of drug ac-
tivity with declining pH. The mechanism involves pH-sensitive NP sur-
face charge-switching, whichis achieved by selective protonation of the
imidazole groups of PLH at low pH. PLGA-PLH-PEG-encapsulated van-
comycin demonstrates reduced loss of efcacy at low pH, with a 1.3-
fold increase in the minimum inhibitory concentration compared to
2.0-fold and 2.3-fold increases for free- and PLGA-PEG-encapsulated
vancomycin, respectively. PLGA-PLH-PEG NPs are a rst step towards
developing systemically administered drug carriers that can target
and potentially treat Gram-positive, Gram-negative, or polymicrobial
infections associated with acidity.
4. Discussion and future aspects
In recent years, the growth of resistant strains of bacteria has been
accompanied by a dearth of new antibiotics, especially those against
Gram-negative bacteria [164]. As a consequence, it is urgent to develop
strategies to preserve the activity of existing antimicrobial drugs. De-
spite very efcient antibacterial activity in vitro, some antibiotics cannot
provide sufcient therapeutic value through the traditional administra-
tion routes, mainly because of limited half-lives in vivo, toxicity, or weak
biodistribution and pharmacokinetics [165]. These limitations may be
overcome by sophisticated delivery systems capable of a coordinated
control over the release of their contents. Cationic antimicrobial pep-
tides have shown immense potential as antimicrobial agents for the
combating of drug resistant bacteria [166170]. However, their hydro-
lytic degradation in biological uids and cytotoxicity seriously limit
their in vivo performance. Devore and colleagues developed polyelec-
trolyte nanoparticle complexes of novel self-assembling anionic graft
copolymers for protecting peptides from degradation in human plasma
[171]. The nanocomplexes can substantially protect the peptides from
degradation in human plasma for at least 24 h and retain some or all
of the peptide's antimicrobial activity against a clinically relevant strain
of S. aureus.
In addition, nanoparticles have the potential to enhance antibacteri-
al activity against extracellular pathogens and in particular may over-
come bacterial drug resistance [172]. Among several mechanisms of
antibiotic resistance in Gram-negative bacteria, a major problem is the
low outer membrane permeability which contributes to multi-drug
resistance. The development of methods to overcome this permeability-
mediated resistance is an important therapeutic goal. Nanoparticles
that can deliver antibiotics into bacterial cells have the ability to over-
come this resistance. Liposomal antibiotic formulations have been
shown to overcome bacterial membrane impermeability and antibiotic
resistance phenomena by fusing with the bacterial outer membrane
and deliver their contents into bacterial cells [173175]. Azithromycin-
loaded PLGA nanoparticles have been shown to be more effective than
pure azithromycin against Salmonella typhi, with nanoparticles showing
equal antibacterial effect at one eighth the concentration of the intact
drug [172]. Folic acid tagged chitosan nanoparticles were also used as
Trojan horse to deliver vancomycin into bacterial cells, which enhanced
the transport of vancomycin across epithelial surfaces and exhibited
more efcient antimicrobial activity against vancomycin sensitive
and resistant S. aureus strains [176]. In another study, an articial
triscatecolate siderophore with a tripodal backbone and its conju-
gates with ampicillin and amoxicillin, which use energy-dependent
active bacterial iron uptake systems to bypass the Gram-negative
outer membrane permeability barrier, exhibited signicantly
enhanced in vitro antibacterial activities against Gram-negative spe-
cies, especially against P. aeruginosa [177]. Very recently, Yang and
colleges reported that codelivery of membrane disrupting polymers
with commercial antibiotics shows high synergism towards difcult-
to-kill P. aeruginosa [178]. When added with 15.6 mg L
1
polymer
(with a MIC at 500 mg L
1
), the minimum bactericidal concentrations
(MBC) of the doxycycline decreased from 20 mg L
1
to 2.5 mg L
1
.
And when 31.5 mg L
1
polymer was added, the MBC of the antibiotic
decreased to 1.0 mg L
1
. The synergistic combinations of macromolec-
ular antimicrobial withcommercial antibiotics may provide a promising
way for combating multi-drug resistance.
As a common and important form of post-transcriptional gene con-
trol in bacteria, RNA silencing is a promising strategy to inhibit bacterial
gene expression for the development of species-specic antibiotics
[179,180] and pharmacological agents to prevent the development of
antibiotic resistance [181,182]. The challenge in achieving effective
RNA silencing lies in optimizing intracellular delivery across stringent
bacterial cell barriers to obtain sufcient intracellular concentrations
of nucleobase oligomers, which are considered to be inherently too
large to achieve efcient cell uptake and in vivo distribution [181]. The
delivery of antisense agents into bacteria remains a signicant chal-
lenge, but opportunities are available to enhance cellular uptake
through encapsulation within nanoparticles. Anionic liposome has
been developed for encapsulating and delivering antisense nucleobase
oligomers [183,184]. The treatment of encapsulated complexes of a spe-
cic anti-mecA phosphorothioate oligodeoxynucleotide (PS-ODN833)
and polycation polyethylenimine inhibits mecA expression, which
confers -lactam resistance, leads to the restoration of susceptibility in
methicillin-resistant S. aureus to existing -lactam antibiotics, and,
nally, rescues mice from lethal sepsis [184]. These strategies have
inspired us to use a polymeric particle delivery system to overcome
the antibiotic resistance of bacteria, since polymer particles are more
stable than liposomes in biological uids and during storage and can
10.1016/j.addr.2014.02.002
be designed for the appropriate application to a specic bacterial strain
and the unique microenvironment of each infection site.
However, there are very few drugs on the market that have been
formulated with polymeric micro/nanoparticles, owing to the relative
toxicity of some of the polymers and organic solvents used. More
work is necessary to push towards the application of these promising
therapeutic tools for use against bacterial infection.
Acknowledgments
This work was supported by the National Basic Research Programof
China (973 Programs 2013CB933900, 2010CB934001, 2012CB932500)
and the National Natural Science Foundation of China (21304082,
51125012, 51390482).
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