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Please cite this article in press as: A. Kumari, et al., Biodegradable polymeric nanoparticles based drug delivery systems, Colloids Surf. B:Biointerfaces (2009), doi:10.1016/j.colsurfb.2009.09.001
ARTICLE IN PRESS
GModelCOLSUB-3781; No.of Pages18Colloids and Surfaces B: Biointerfaces
xxx (2009) xxx–xxx
Contents lists available atScienceDirect
ColloidsandSurfacesB:Biointerfaces
 journal homepage:www.elsevier.com/locate/colsurfb
Review
Biodegradable polymeric nanoparticles based drug delivery systems
Avnesh Kumari, Sudesh Kumar Yadav, Subhash C. Yadav
∗
Biotechnology Division, Institute of Himalayan Bioresource Technology, CSIR, Palampur, HP 176061, India
a r t i c l e i n f o
 Article history:
Received 18 June 2009Received in revised form 28 August 2009Accepted 2 September 2009
Available online xxx
Keywords:
BiodegradablePolymeric nanoparticlesEncapsulation efficiencyPolylactic acidPolylactic acid co-glycolic acidPoly-
-caprolactoneChitosan
a b s t r a c t
Biodegradablenanoparticleshavebeenusedfrequentlyasdrugdeliveryvehiclesduetoitsgrandbioavail-ability, better encapsulation, control release and less toxic properties. Various nanoparticulate systems,general synthesis and encapsulation process, control release and improvement of therapeutic value of nanoencapsulated drugs are covered in this review. We have highlighted the impact of nanoencapsula-tionofvariousdiseaserelateddrugsonbiodegradablenanoparticlessuchasPLGA,PLA,chitosan,gelatin,polycaprolactone and poly-alkyl-cyanoacrylates.
© 2009 Elsevier B.V. All rights reserved.
Contents
1. Introduction..........................................................................................................................................
00
2. Synthesis and encapsulation of drugs in polymeric nanoparticles..................................................................................
00
3. Poly-
d
,
l
-lactide-co-glycolide (PLGA) ................................................................................................................
00
3.1. Encapsulation of various anticancer drugs on PLGA nanoparticles..........................................................................
00
3.1.1. 9-Nitrocamptothecin...............................................................................................................
00
3.1.2. Paclitaxel............................................................................................................................
00
3.1.3. Cisplatin.............................................................................................................................
00
3.1.4. Xanthones ..........................................................................................................................
00
3.1.5. Rose bengal .........................................................................................................................
00
3.1.6. Triptorelin ..........................................................................................................................
00
3.1.7. Dexamethasone.....................................................................................................................
00
3.2. Encapsulation of diabetes drugs (insulin) on PLGA nanoparticles...........................................................................
00
3.3. Encapsulation of psychotic drugs (haloperidol) on PLGA nanoparticles ....................................................................
00
3.4. Encapsulation of hormones (estradiol) on PLGA nanoparticles .............................................................................
00
3.5. Encapsulation of tetanus drugs on PLGA nanoparticles .....................................................................................
00
4. Polylactic acid (PLA)..................................................................................................................................
00
4.1. Encapsulation of psychotic drugs (savoxepine) on PLA nanoparticles ......................................................................
00
4.2. Encapsulation of restenosis drugs (tyrphostins) on PLA nanoparticles .....................................................................
00
4.3. Encapsulation of hormones (progesterone) on PLA nanoparticles ..........................................................................
00
4.4. Encapsulation of oridonin on PLA nanoparticles.............................................................................................
00
4.5. Encapsulation of protein (BSA) on PLA nanoparticles .......................................................................................
00
5. Poly-
-caprolactone (PCL) ...........................................................................................................................
00
5.1. Encapsulation of anticancer drugs on PCL nanoparticles....................................................................................
00
5.1.1. Tamoxifen...........................................................................................................................
00
5.1.2. Taxol ................................................................................................................................
00
∗
Corresponding author. Tel.: +91 1894233339x397; fax: +91 1894230433.
E-mail address:
subhash@ihbt.res.in(S.C. Yadav).0927-7765/$ – see front matter
© 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.colsurfb.2009.09.001
 
Please cite this article in press as: A. Kumari, et al., Biodegradable polymeric nanoparticles based drug delivery systems, Colloids Surf. B:Biointerfaces (2009), doi:10.1016/j.colsurfb.2009.09.001
ARTICLE IN PRESS
GModelCOLSUB-3781; No.of Pages18
2
A. Kumari et al. / Colloids and Surfaces B: Biointerfaces
 xxx (2009) xxx–xxx
5.2. Encapsulation of diabetes drugs (insulin) on PCL nanoparticles ............................................................................
00
5.3. Encapsulation of clonezepam drugs on PCL nanoparticles ..................................................................................
00
5.4. Encapsulation of antifungal (amphotericin B) drugs on PCL nanoparticles .................................................................
00
6. Chitosan..............................................................................................................................................
00
6.1. Encapsulation of antihormonal (glycyrrhizin) drugs on chitosan nanoparticles............................................................
00
6.2. Encapsulation of insulin on chitosan nanoparticles .........................................................................................
00
6.3. Encapsulation of ocular (cyclosporin A) drugs on chitosan nanoparticles ..................................................................
00
7. Gelatin................................................................................................................................................
00
7.1. Encapsulation of BSA on gelatin nanoparticles ..............................................................................................
00
7.2. Encapsulation of anticancer drug (paclitaxel) on gelatin nanoparticles.....................................................................
00
7.3. Encapsulation of oligonucleotides on gelatin nanoparticles.................................................................................
00
7.4. Encapsulation of anti-HIV drug (didanosine) on gelatin nanoparticles .....................................................................
00
7.5. Encapsulation of antimalarial drug (chloroquine phosphate) onto gelatin nanoparticles..................................................
00
8. Poly-alkyl-cyano-acrylates (PAC)....................................................................................................................
00
8.1. Encapsulation of antibacterial (ampicillin) on poly-alkyl-cyanoacrylates nanoparticles...................................................
00
8.2. Encapsulation of anti-inflammatory (indomethacin) drugs on poly-alkyl-cyanoacrylate nanoparticles...................................
00
8.3. Encapsulation of various anticancer drugs on poly-alkyl-cyanoacrylate nanoparticles ....................................................
00
9. Modification of surface properties...................................................................................................................
00
10. Drug loading and release mechanisms.............................................................................................................
00
11.
Conclusion
.........................................................................................................................................
00
Acknowledgements..................................................................................................................................
00
References...........................................................................................................................................
00
1. Introduction
Nanotechnologyisnowfrequentlyusedforvariousapplicationsin fiber and textiles[1],agriculture[2,3],electronics[4],forensic science[5],space[6]and medical therapeutics[7–11].How- ever, biodegradable nanoparticles are frequently used to improvethe therapeutic value of various water soluble/insoluble medic-inal drugs and bioactive molecules by improving bioavailability,solubility and retention time[12].These nanoparticle–drug for- mulation reduces the patient expenses, and risks of toxicity[13].Nanoencapsulation of medicinal drugs (nanomedicines) increasesdrug efficacy, specificity, tolerability and therapeutic index of corresponding drugs[14–19].These nanomedicines have many advantagesintheprotectionofprematuredegradationandinterac-tion with the biological environment, enhancement of absorptioninto a selected tissue, bioavailability, retention time and improve-ment of intracellular penetration[20].Several disease related drugs/bioactive molecules are suc-cessfully encapsulated to improve bioavailability, bioactivity andcontrol delivery[21–23].Nanomedicines of the dreadful diseases likecancer[24],AIDS[25],diabetes[26],malaria[27],priondisease [28]and tuberculosis[29]are in different trial phase for the test- ing and some of them are commercialized[30,31].Nanomedicine formulation depends on the choice of suitable polymeric systemhaving maximum encapsulation (higher encapsulation efficiency),improvement of bioavailability and retention time. The desirednanomedicines are generally achieved by hit and trial method (nospecific rule) however, the encapsulation process with polymericnanoparticlesareinmoreadvanceconditionincomparisontoothernanoparticle systems[32].These drug nanoformulations (nano- drug) are superior to traditional medicine with respect to controlrelease, targeted delivery and therapeutic impact. These target-ing capabilities of nanomedicines are influenced by particle size,surface charge, surface modification, and hydrophobicity. Amongthese, the size and size distributions of nanoparticles are impor-tant to determine their interaction with the cell membrane andtheir penetration across the physiological drug barriers. The sizeof nanoparticles for crossing different biological barriers is depen-dent on the tissue, target site and circulation[33].For the cellular internalization of the nanoparticles, surface charge is importantin determining whether the nanoparticles would cluster in bloodflow or would adhere to, or interact with oppositely charged cellsmembrane[34].Cationic surface charge is desirable as it promotes interaction of the nanoparticles with the cells and hence increasesthe rate and extent of internalization[12].For targeted delivery, persistence of nanoparticles is required in systemic circulation of the body. But conventional nanoparticles with hydrophobic sur-face are rapidly opsonized and massively cleared by the fixedmacrophagesofthemononuclearphagocyticsystem(MPS)organs.For increasing circulation time and persistence in the blood, sur-face of conventional nanoparticles are modified with differentmolecules. Coating of hydrophilic polymers can create a cloud of chains at the particle surface which will repel plasma proteins[35].Finally, the performance of nanoparticles
in vivo
is influencedby morphological characteristics, surface chemistry, and molec-ular weight. Surface modified nanoparticles have anti-adhesiveproperties by virtue of the extended configuration on the par-ticle surface which acts as steric barrier reducing the extent of clearance by circulating macrophages of the liver and promotingthe possibility of undergoing enhanced permeation process[12].Release mechanism can be modulated by the molecular weight of the polymer used. Higher the molecular weight of polymer slowerwill be the
in vitro
release of drugs[36].Careful design of these delivery systems with respect to target and route of administra-tionmaysolvesomeoftheproblemsfacedbynewclassesofactivemolecules.The synthesis process of biodegradable nanoparticles has beenreviewed earlier[37].Lowman group has published a review on the synthesis, surface modification, targeted delivery and releasecharacteristic of biodegradable nanoparticles[38].The synthesis and nanomedicine formulation of chitosan[39],PLGA[40],PLA [41]are well reviewed. However, the encapsulation of variousdiseases related drugs with various biodegradable nanoparticlesand their applications are not reviewed yet. We have reviewedthe encapsulation effects of different drug on various polymericbiodegradable nanoparticles, and its impact upon surface modi-fication, bioavailability and drug release mechanisms. This paperreviewed the formulation of nanomedicine of known drugs of cancer, diabetes, malaria, etc., on the PLA, PLGA, PCL, chitosan,gelatin and poly-alkyl-acyanoacrylate nanoparticles. This reviewdoes not have the details of the synthesis and encapsulation of drug molecules. However, it provides the basic approach and nan-otechnology applications in the therapeutic medicines of variousdiseases.
 
Please cite this article in press as: A. Kumari, et al., Biodegradable polymeric nanoparticles based drug delivery systems, Colloids Surf. B:Biointerfaces (2009), doi:10.1016/j.colsurfb.2009.09.001
ARTICLE IN PRESS
GModelCOLSUB-3781; No.of Pages18
 A. Kumari et al. / Colloids and Surfaces B: Biointerfaces
 xxx (2009) xxx–xxx
3
Fig. 1.
Type of biodegradable nanoparticles
: According to the structural organiza-tionbiodegradablenanoparticlesareclassifiedasnanocapsule,andnanosphere.Thedrug molecules are either entrapped inside or adsorbed on the surface. (Originallyadapted from[39]but modified.)
2. Synthesis and encapsulation of drugs in polymericnanoparticles
Polymeric nanoparticles have been synthesized using variousmethods[42]according to needs of its application and type of drugstobeencapsulated.Thesenanoparticlesareextensivelyusedfor the nanoencapsulation of various useful bioactive moleculesand medicinal drugs to develop nanomedicine. Biodegradablepolymeric nanoparticles are highly preferred because they showpromise in drug delivery system. Such nanoparticles providecontrolled/sustained release property, subcellular size and bio-compatibility with tissue and cells[43].Apart from this, these nanomedicines are stable in blood, non-toxic, nonthrombogenic,nonimmunogenic, noninflammatory, do not activate neutrophils,biodegradable, avoid reticuloendothelial system and applicable tovariousmoleculessuchasdrugs,proteins,peptides,ornucleicacids[11].The general synthesis and encapsulation of biodegradablenanomedicinesarerepresentedinFig.1.Thedrugmoleculeseither boundtosurfaceasnanosphereorencapsulatedinsideasnanocap-sules.For the past two decades, countless work has been conductedto develop most effective nanomedicines from biocompatibleand biodegradable nanopolymers[44].The role of nanosystems for drug delivery through oral, nasal, ocular administration isreviewed by Alonso[45].Pinto Reis et al.[42]reviewed the var- ious methods of synthesis and encapsulation of different bioactivemolecules on nanoparticles. Most of the reported methods are fre-quently used for the synthesis of biodegradable nanomedicines.Some of the commonly used methods are concisely describedin this review along with each section and their encapsulation.The administration, activity and therapeutic importance of somemedicinal drugs on different nanosystems are different, for exam-ple taxol (anticancer drug) nanomedicine have 100% and 20%encapsulation efficiency on PLGA[24]and PCL[30]nanodevices respectively. However, the therapeutic activity and stability of PCLnanomedicines are reasonably high than PLGA nanomedicine[30].This part of review gave a brief analysis and sound informationabout current research in nanobiotechnology and their impact ontherapeutics, development of novel nanomedicines, preparationprocess and their surface modification for the improvement of therapeutics (Table 1A).The most commonly and extensively used polymeric nanoparticles (poly-
d
,
l
-lactide-co-glycolide, polylacticacid,poly-
-caprolactone,poly-alkyl-cyanoacrylates,chitosanandgelatin),theirtherapeuticadvantages,generalsynthesisandencap-sulationofvariousdiseaserelateddrughavebeendescribedinthispart of the review.
3. Poly-
d
,
l
-lactide-co-glycolide (PLGA)
PLGA (poly-
d
,
l
-lactide-co-glycolide) is one of the most suc-cessfully used biodegradable nanosystem for the development of nanomedicines because it undergoes hydrolysis in the body toproduce the biodegradable metabolite monomers, lactic acid andglycolicacid(Fig.2).Sincethebodyeffectivelydealswiththesetwo monomers, there is very minimal systemic toxicity associated byusing PLGA for drug delivery or biomaterial applications.PLGA nanoparticles have been mostly prepared byemulsification–diffusion[46],solvent emulsion–evaporation [36],interfacial deposition[42]and nanoprecipitation method [47](Fig. 3). Generally in emulsification–diffusion method, the PLGApolymersaredissolvedinorganicsolvent(EtAc,MEK,PC,BA,etc.), poured and separated in aqueous phase having stabilizer andsubsequently emulsified by homogenizer. In solvent evaporationmethod, the polymers are dissolved in volatile organic solvent(DCM, acetone, CHCl
3
, EtAc, etc.) and poured into continuouslystirring aqueous phase with or without emulsifier/stabilizerand sonicated. Interfacial deposition methods have been usedfor the formation of both nanocapsule and nanospheres. Thenanoparticles are synthesized in the interfacial layer of water andorganic solvent (water miscible) and finally the nanoparticles are
Fig. 2.
Hydrolysis of PLGA nanoparticles
: PLGA nanoparticles are biologically hydrolyzed in acidic medium into lactic and glycolic acid. These hydrolysis products have beenmetabolized in TCA cycle.
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