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Review
Department of Chemistry, Polymer Research Group, Karnatak University, Dharwad 580 003, India
b
Department of Chemistry, Southwest Texas State University, San Marcos, TX 78666, USA
Received 12 June 2000; accepted 28 September 2000
Abstract
This review presents the most outstanding contributions in the field of biodegradable polymeric nanoparticles used as drug
delivery systems. Methods of preparation, drug loading and drug release are covered. The most important findings on surface
modification methods as well as surface characterization are covered from 1990 through mid-2000. 2001 Elsevier
Science B.V. All rights reserved.
Keywords: Nanoparticle; Method of preparation; Surface modification; Drug delivery; Drug targeting
1. Introduction
Over the past few decades, there has been considerable interest in developing biodegradable
nanoparticles (NPs) as effective drug delivery devices. Various polymers have been used in drug
delivery research as they can effectively deliver the
drug to a target site and thus increase the therapeutic
benefit, while minimizing side effects [1]. The
controlled release (CR) of pharmacologically active
agents to the specific site of action at the therapeutically optimal rate and dose regimen has been a
major goal in designing such devices. Liposomes
have been used as potential drug carriers instead of
conventional dosage forms because of their unique
advantages which include ability to protect drugs
from degradation, target the drug to the site of action
*Corresponding author. Fax: 191-836-747-884.
E-mail address: rrist@bgl.vsnl.net.in (T.M. Aminabhavi).
0168-3659 / 01 / $ see front matter 2001 Elsevier Science B.V. All rights reserved.
PII: S0168-3659( 00 )00339-4
2. Preparation of nanoparticles
Conventionally, NPs have been prepared mainly
by two methods: (i) dispersion of the preformed
polymers; and (ii) polymerization of monomers.
Fig. 1. Schematic diagram of the SAS method: PV1 and PV2 are
two volumetric pumps, N is nozzle, P is precipitation vessel, MV
is micrometric valve and EV is expansion vessel.
Fig. 2. Schematic representation for the production of poly(alkylcyanoacrylate) nanoparticles by anion polymerization.
3. Drug loading
A successful NP system may be the one, which
has a high loading capacity to reduce the quantity of
the carrier required for administration. Drug loading
into the NPs is achieved by two methods: one, by
incorporating the drug at the time of NP production
or secondly, by adsorbing the drug after the formation of NPs by incubating them in the drug solution.
It is thus evident that a large amount of drug can be
entrapped by the incorporation method when compared to the adsorption [76,77]. Adsorption isotherms for the NP/ drug delivery system give vital
information on the best possible formulation, the
drug binding capacity onto the surface of NPs and
the amount of drug adsorbed. For instance, Couvreur
et al. [78] reported the adsorption of two antineoplastic drugs viz, dactinimycin and methotrexate onto
poly(methylcyanoacrylate)
and
poly(ethylcyanoacrylate). It was observed that methotrexate was bound to the NPs to a lesser extent than
dactinimycin. Generally, in the case of PACA, it is
observed that longer the alkyl chain length higher the
affinity for the drugs. The capacity of adsorption is
thus related to the hydrophobicity of the polymer and
the specific area of the NPs. In case of entrapment
method, an increase in concentration of the monomer, increases the association of drug, but a reverse
trend is observed with the drug concentration in the
dispersed solution. This observation was further
substantiated by Radwan [79] who studied the effect
of monomer concentration on % drug loading. These
results indicate that there is a need to optimize the
amount of monomer available for the drug entrapment.
The type of surface-active materials and stabilizers
has an effect on drug loading [80]. Chukwu et al.
[81] studied the adsorption of different psychopharmacological agents onto NPs of poly(isobutylcyanoacrylate), PIBCA, in the pH range
between 2.0 and 7.4. Adsorption of drugs onto NPs
followed the Langmuir mechanism [82,83]. In
another study [84], a dielectric method was used to
investigate the adsorption of b-blockers onto PIBCA
NPs. In this method, the NP suspensions were taken
into a capacitance cell, exposed to a high-frequency
field (10 MHz) and the complex impedance was
measured. This technique is rapid and inexpensive
4. Drug release
Drug release from NPs and subsequent biodegradation are important for developing the successful
formulations. The release rates of NPs depend upon:
(i) desorption of the surface-bound / adsorbed drug;
(ii) diffusion through the NP matrix; (iii) diffusion
(in case of nanocapsules) through the polymer wall;
(iv) NP matrix erosion; and (v) a combined erosion /
diffusion process. Thus, diffusion and biodegradation
govern the process of drug release.
Methods to study the in vitro release are: (i)
side-by-side diffusion cells with artificial or biological membranes; (ii) dialysis bag diffusion technique; (iii) reverse dialysis sac technique; (iv) ultracentrifugation; (v) ultrafiltration; or (vi) centrifugal
ultrafiltration technique. Despite the continuous efforts in this direction, there are still some technical
difficulties to study in vitro drug release from NPs
[86,87]. These are attributed to the separation of NPs
from the release media. In order to separate NPs and
to avoid the tedious and time-consuming separation
techniques, dialysis has been used; here, the suspension of NPs is added to the dialysis bags / tubes of
different molecular mass cut-off. These bags are then
incubated in the dissolution medium [8890].
Another technique involves the use of a diffusion
cell consisting of donor and acceptor compartments;
this technique was used to separate through the
artificial / biological membranes [91]. In this method,
kinetic study was not performed under the perfect
sink conditions, because the NPs were not directly
diluted in the release media, but were separated from
10
23%, the MPOE chain adopts a brush-like configuration forming a sterically-uncharged barrier, thereby
reducing the zeta potential and phagocytosis.
Govender et al. [114] examined the drug-encapsulation characteristics of PLAPLA NPs using
procaine hydrochloride, a water-soluble drug. The
PLAPEG NPs were produced by the nano-precipitation technique. The drug-entrapment efficiencies of
these NPs were compared with those of PLGA NPs.
Kim et al. [115] used the ESCA method to evaluate
the presence of PEG on the surface of indomethacinloaded Me-PEGPLA NPs. The in-vitro cytotoxicity
of these NPs did not show any remarkable cytotoxicity against the normal human fibroblast cells.
The optimum surface density of PEG on NPs
plays an important role in steric repulsion. These
NPs have shown a lower accumulation in the liver,
but the observed high spleen uptake is due to the
removal of PEG coating from the surface of NPs, an
important property in spleen targeting [116]. In
addition, the distance between PEG chains on the
surface of NPs is critical to avoid the adsorption of
plasma proteins. For instance, a decrease in the
distance between PEG chains on the surface from 6.2
to 5.1 nm drastically decreases the adsorption of
apolipoproteins up to 90%. This further confirms that
the density of hydrophilic segment on the surface of
NPs is important in opsonization. However, any
further decrease in this distance did not show
significant effects on the adsorption of plasma proteins [117].
Peracchia et al. [118] used the emulsification and
solvent evaporation method to prepare the diblock
Me-PEGPLA copolymeric NPs containing 20 and
33% of lidocaine. They confirmed high-density of
the surface PEG by ESCA. However, the size of NPs
produced by the block copolymer was twice as high
as those of PLGA NPs. This was attributed to an
increase in the chain length of PEG. Peracchia et al.
[119,120] reported the chemical coupling of PEG
with PBCA NPs prepared by emulsion polymerization in the presence of PEG, Me-PEG and (Me) 2 PEG. Polymerization was possible only in the presence of PEG and Me-PEG as hydroxyl group was
necessary for polymerization and association of PEG
on the surface of NPs. Higher PEG density was
observed on the surface of NPs when Me-PEG was
used. A decrease in hydrophobicity was observed for
PEO block copolymers (Plunoric) and poly(e-caprolactone) by bulk polymerization [125]. The size of
the NPs prepared varied from 116 to 196 nm,
depending upon the type of copolymer used.
11
12
ty constant of the inclusion drug / parent g-cyclodextrin and with a decrease in water solubility.
The PIBCA NPs were prepared by the anionic
polymerization of isobutylcyanoacrylate in 0.01 M
HCl containing 1% poloxamer-188 and in the presence of cyclodextrins. The size, zeta potential and
cyclodextrin content were influenced by the nature of
cyclodextrin. The smallest size particles were obtained from hydroxypropyl b-cyclodextrin, but the
highest cyclodextrin content was obtained for bcyclodextrin. The cyclodextrin NPs or the polymeric
NPs containing cyclodextrin were useful in targeting
the water-insoluble drugs through oral or parentral
route. The presence of cyclodexrins in these NPs has
drastically reduced the surface negativity probably
due to their hydrophilicity; hence, the cyclodextrin
coated NPs may help in avoiding the MPS.
(alkylcyanoacrylate) NPs are superior over the uncoated NPs to transport drugs across BBB.
Recently, investigations have been carried out
[145] with PBCA NPs as well as with the nonbiodegradable polystyrene (PS) NPs (200 nm in
diameter) to study the transport of analgesic peptide,
dalargin to the brain. Its entry into the CNS of the
mice was evaluated using the tail-flick procedure.
Locomotor activity measurements were performed to
compare the toxicity of NPs. BBB permeability of
PBCA NPs was studied in-vitro using a co-culture of
bovine brain capillary endothelial cells and rat
astrocytes. Dalargin associated with PBCA NPs and
polysorbate-80 induced a potent and prolonged analgesia, which was not observed by using polystyrene
NPs, but not using the PBCA NPs. Locomotor
activity dramatically decreased in the mice dosed
with PBCA NPs, but not with the polystyrene NPs.
The in-vitro and in-vivo results suggested that the
PBCA NPs induce a nonspecific opening of the BBB
in the presence of polysorbate-80 allowing the
transport of dalargin into the CNS. Although
polysorbate-80 coated PBCA NPs are useful in
increasing the penetration of drugs into the CNS,
potential therapeutic applications are limited because
of the high systemic NP concentration needed to
deliver drugs to the CNS.
In an effort to deliver anticancer drugs to the brain
using NPs, Gulyaev et al. [146] demonstrated that
the brain concentration of systemically administered
doxorubicin was enhanced by more than 60-fold by
binding it to polysorbate-80 coated PBCA NPs.
Doxorubicin was selected as a model drug due to its
potent antitumor activity and because the drug is not
able to cross the BBB by i.v. injection. Polysorbate80 coated NPs reached the brain intact and released
the drug after endocytosis by the brain blood vessel
endothelial cells. High brain concentrations achieved
in this study suggested a significant improvement in
the treatment of brain tumors.
Alyautdin et al. [147] studied the efficiency of
polysorbate-80 coated PBCA NPs in crossing BBB
to deliver the water-insoluble analgesic drug, lopermide, in mice. Intravenous injection of the
polysorbate-80 coated NPs resulted in a long and
significant analgesic effect, which was measured by
the tail flick method, while the uncoated NPs were
unable to produce analgesia. Alyautdin et al. [141]
13
14
7. Conclusions
The use of biodegradable polymers for the CR of
therapeutic agents is now well established. Although
currently there are only a small number of commercially available products that utilize this technology
(e.g., Lupron Depot ), these polymers have great
utility for the CR of several drugs like vaccines,
human growth hormone, insulin, anti-tumor agents,
contraceptives and also vaccines. Long circulation of
drugs in the body is the key in successful drug
delivery and drug targeting to the site of action.
Many polymeric NPs have been developed for this
purpose. Certainly, surface modification is useful in
achieving these goals. From the polymer chemistry
viewpoint, it is important to synthesize newer polymers and copolymers to match the hydrophilic and
hydrophobic properties. Production of NPs using the
environmentally friendly processes like supercritical
fluids is quite a promising area of research to
develop the products that are free from the unwanted
toxic residual solvents. Although many important
goals have been reached in achieving stabilization of
drugs in circulation, yet more investigations are
needed to develop the newer materials in this area.
Acknowledgements
We immensely thank the Council of Scientific and
Industrial Research, New Delhi, India [Grant [
80(0025)97 / EMR-II] for a major financial support
of this study. Dr. Walter E. Rudzinski thanks the
References
[1] J. Kreuter, Nanoparticles, in: J. Kreuter (Ed.), Colloidal Drug
Delivery Systems, Marcel Dekker, New York, 1994, pp.
219342.
[2] C.G. Knight (Ed.), Liposomes From Physical Structure To
Therapeutic Applications, Elsevier, Amsterdam, 1981.
[3] R. Langer, Biomaterials in drug delivery and tissue engineering: One laboratorys experience, Acc. Chem. Res. 33 (2000)
94101.
[4] R.P. Lanza, R. Langer, W.L. Chick, Principles of Tissue
Engineering, in: Academic Press, Austin, TX, 1997, pp.
405427.
[5] L.B, Peppas, Recent advances on the use of biodegradable
microparticles and nanoparticles in the controlled drug
delivery, Int. J. Pharm. 116 (1995) 19.
[6] A. Zimmer, J. Kreuter, Microspheres and nanoparticles used
in ocular drug delivery systems, Adv. Drug. Deliv. Rev. 16
(1995) 6173.
[7] P. Couvreur, L. Grislain, V. Lenaerts, F. Brasseur, P. Guiot,
in: P. Guiot, P. Couvreur (Eds.), Polymeric Nanoparticles and
Microspheres, CRC Press, Boca Raton, Florida, 1986.
[8] D.F. Raney, Biomimetic transport, rational drug delivery,
Biochem. Pharmacol. 59 (2000) 105114.
[9] K.E. Uhrich, S.M. Cannizzaro, R.S. Langer, K.M. Shakessheff, Polymeric systems for controlled drug release, Chem.
Rev. 99 (1999) 31813198.
[10] C. Monfardini, F.M. Veronese, Stabilization of substances in
circulation, Bioconjug. Chem. 9 (1998) 418450.
[11] V.P. Torchilin, Polymer-coated long-circulating microparticulate pharmaceuticals, J. Microencapsul. 15 (1998) 119.
[12] D.L. Wise, T.D. Fellman, J.E. Sanderson, R.L. Wentworth,
Lactide / glycolide acid polymers, in: G. Geregoriadis (Ed.),
Drug Carriers in Biology and Medicine, Academic, London,
1979, pp. 237270.
[13] T.M. Jackanicz, H.A. Nash, D.L. Wise, J.B. Gregory, Poly
lactic acid as a biodegradable carrier for contraceptive
steroids, Contraception 8 (1973) 227234.
[14] L.C. Andersson, D.L. Wise, J.F. Howes, An injectable
sustained release fertility control system, Contraception 13
(1976) 375384.
[15] C.G. Pitt, M.M. Gratzi, A.R. Jeffcot, R. Zweidinger, A.
Schindler, Sustained release drug delivery systems II: factors
affecting release rate for poly(e-caprolactone) and related
biodegradable polyesters, J. Pharm. Sci. 68 (1979) 1534
1538.
[16] C.G. Pitt, T.A. Marks, A. Schindler, Biodegradable drug
delivery systems based on aliphatic polyesters: application to
contraceptives and narcotic antagonists, in: R. Baker (Ed.),
Controlled Release of Bioactive Materials, Academic, New
York, 1980, pp. 1943.
15
16
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
evading hydrophilic nanoparticles, Proc. Intern. Symp. Control. Rel. Bioact Mater. 25 (1998) 168169.
R. Gref, Y. Minamitake, M.T. Peracchia, V. Trubetskoy, V.P.
Torchilin, R. Langer, Biodegradable long circulating polymeric nanospheres, Science 18 (1994) 16001603.
M. Amiji, K. Park, in: S.W. Shalaby, Y. Ikada, R. Langer, J.
Williams, (Eds.), Polymers of Biological Significance, ACS
Symp. Ser. 540, Washington, DC, 1994.
P. Calvo, C. Remunan-Lopez, J.L. Vila-Jato, M.J. Alonso,
Novel hydrophilic chitosan and chitosan / polyethylene oxide
nanoparticles as protein carriers, J. Appl. Polym. Sci. 63
(1997) 125132.
P. Calvo, C. Remunan-Lopez, J.L. Vila-Jato, M.J. Alonso,
Chitosan and chitosan / ethylene oxidepropylene oxide
block copolymer nanoparticles as novel carriers for proteins
and vaccines, Pharm. Res. 14 (1997) 14311436.
R. Fernandez-urrusuno, P. Calvo, C. Remunan-Lopez, J.L.
Vila-Jato, M.J. Alonso, Enhancement of nasal absorption of
insulin using chitosan nanoparticles, Pharm. Res. 16 (1999)
15761591.
P. Calvo A.S. Boughaba, M. Appel, E. Fattal, M.J. Alonso, P.
Couvreur, Oligonucleotidechitosan nanoparticles as new
gene therapy vector, Proc. 2nd World Meeting APGI /APV
Paris, 1998, pp. 11111112.
H.-Q. Mao, K. Ray, S.M. Walsh, J.T. August, K.W. Leong,
DNAchitosan nanoparticles for the gene delivery, Proc.
Intern. Symp. Control. Release. Bioact. Mater. 23 (1996)
401402.
K. Ray, H.-Q. Mao, K.Y. Lin, S.-K. Huang, K.W. Leong,
Oral immunization with DNAchitosan nanoparticles, Proc.
Intern. Symp. Control. Release. Bioact. Mater. 26 (1999)
348349.
V.L. Truong-Le, H. Mao, S. Walsh, K.W. Leong, J.T. August,
Delivery of DNA vaccine using gelatinDNA nanoparticles,
Proc. Intern. Symp. Control. Rel. Bioact. Mater. 24 (1997)
3940.
X.-X. Tian, M.J. Groves, Formulation and biological activity
of antineoplastic proteoglycans derived from Mycobacterium
vaccae in chitosan nanoparticles, J. Pharm. Pharmacol. 51
(1999) 151157.
H. Tokumitsu, H. Ichikawa, Y. Fuukumori, Chitosan
gadopenteic acid complex nanoparticles for gadolinium
neutron-capture therapy of cancer: preparation by novel
emulsiondroplet coalescence technique and characterization, Pharm. Res. 16 (1999) 18301835.
C. Vautheir, I. Aynie, P. Couvreur, E. Fattal, Pharmacokinetic
and tissue disposition of oligonucleotide associated with
alginate nanoparticles, Proc. Intern. Symp. Control. Rel.
Bioact. Mater. 25 (1998) 228229.
T. Jung, A. Breitenbach, T. Kissel, Sulfobutylated poly(vinyl
alcohol)-graft-poly(lactide-co-glycolide) facilitate the preparation of small negatively charged biodegradable nanospheres for protein delivery, J. Control. Rel. 67 (2000) 157
169.
A. Breitenbach, G. Nykamp, T. Kissel, Self-assembling
colloidal carriers for protein delivery: nanoparticulate polymer protein conjugates with novel water soluble biodegra-
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[86]
[87]
[88]
[89]
[90]
17
18
Micali, P.M. Furneri, Pefloxacin mesilate- and ofloxacinloaded polyethylcyanoacrylate nanoparticles; characterization
of the colloidal drug carrier formulation, J. Pharm. Sci. 84
(1995) 895901.
[91] G. Cavallaro, M. Fresta, G. Giammona, G. Puglisi, A. Villari,
Entrapment
of
b-lactams
antibiotics
in
polyethylcyanoacrylate nanoparticles: studies on the possible in
vivo application of this colloidal delivery system, Int. J.
Pharm. 111 (1994) 3141.
[92] M.Y. Leavy, S. Benita, Drug release from submicron O / W
emulsion: A new in vitro kinetic evaluation model, Int. J.
Pharm. 66 (1990) 2937.
[93] R. Jalil, J.R. Nixon, Biodegradable poly(lactic acid) and
poly(lactide-co-glycolide) microcapsules: problems associated with preparative techniques and release properties, J.
Microencapsul. 7 (1990) 297325.
[94] B. Magenheim, M.Y. Levy, S. Benita, A new in vitro
technique for the evaluation of drug release profiles from
colloidal carriers-ultrafiltration technique at low pressure, Int.
J. Pharm. 94 (1993) 115123.
[95] J.M. Rodrigues Jr, H. Fessa, C. Bories, F. Pusieux, J.-Ph.
Devissaguet, Premaquine-loaded poly(lactide) nanoparticles:
physicochemical study and acute tolerance in mice, Int. J.
Pharm. 126 (1995) 253260.
[96] M. Polakovic, T. Gorner, R. Gref, E. Dellacherie, Lidocaine
loaded biodegradable nanospheres. II. modeling of drug
release, J. Control. Rel. 60 (1999) 169177.
[97] Z. Lu, J. Bei, S. Wang, A method of the preparation of
polymeric nanocapsules without stabilizer, J. Control. Rel.
61 (1999) 107112.
[98] H. Muller, K.M. Willis, Surface modification of i.v. injectable biodegradable nanoparticles with poloxamer polymers
and poloxamine 908, Int. J. Pharm. 89 (1993) 2531.
[99] C.J. Van Oss, Phagocytosis as a surface phenomenon, Annu.
Rev. Microbiol. 32 (1978) 1939.
[100] E. Allemann, G. Patricia, J.C. Leroux, B. Luc, R. Gurnay,
Kinetics of blood component-adsorption on poly( D,L-lactide) nanoparticles: Evidence of compliment C 3 component
involvement, J. Biomed. Mater. Res. 37 (1997) 229234.
[104] M. Luck,
K.F. Pistel, Y. Li, T. Blunk, R.H. Muller,
T.
Kissel, Plasma protein adsorption on biodegradable microspheres consisting of poly( D,L-lactide-co-glycolide), poly( Llactide) or ABA triblock copolymers containing poly(oxyethylene), J. Control. Rel. 55 (1998) 107120.
[120]
[121]
[122]
[123]
[124]
[125]
[126]
[127]
[128]
[129]
[130]
[131]
19
20
[148]
[149]
[150]
[151]
[152]