Abstract
During the past decades many synthetic polymers have been studied for nanomedicine applications and in particular as drug delivery systems. For this purpose, polymers must be non-toxic, biodegradable, and biocompatible. Polylactic-co-glycolic acid (PLGA) is one of the most studied polymers due to its complete biodegradability and ability to self-assemble into nanometric micelles that are able to entrap small molecules like drugs and to release them into body in a time-dependent manner. Despite fine qualities, using PLGA polymeric nanoparticles for in vivo applications still remains an open challenge due to many factors such as poor stability in water, big diameter (150–200 nm), and the removal of these nanocarriers from the blood stream by the liver and spleen thus reducing the concentration of drugs drastically in tumor tissue. Polyethylene glycol (PEG) is the most used polymers for drug delivery applications and the first PEGylated product is already on the market for over 20 years. This is due to its stealth behavior that inhibits the fast recognition by the immune system (opsonization) and generally leads to a reduced blood clearance of nanocarriers increasing blood circulation time. Furthermore, PEG is hydrophilic and able to stabilize nanoparticles by steric and not ionic effects especially in water. PLGA–PEG block copolymer is an emergent system because it can be easily synthesized and it possesses all good qualities of PLGA and also PEG capability so in the last decade it arose as one of the most promising systems for nanoparticles formation, drug loading, and in vivo drug delivery applications. This review will discuss briefly on PLGA-b-PEG synthesis and physicochemical properties, together with its improved qualities with respect to the single PLGA and PEG polymers. Moreover, we will focus on but in particular will treat nanoparticles formation and uses as new drug delivery system for nanomedical applications.
Similar content being viewed by others
References
Abuchowski A, Van Es T, Palczuk NC, Davis FF (1977) Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J Biol Chem 252:3582–3586
Alex R, Bodmeier R (1989) Encapsulation of water-soluble drugs by a modified solvent evaporation method: effect of process and formulation variables on drug entrapment. J Microencapsul 7:347–355
Ashjari M, Khoee S, Mahdavian AR, Rahmatolahzadeh R (2012) Self-assembled nanomicelles using PLGA–PEG amphiphilic block copolymer for insulin delivery: a physicochemical investigation and determination of CMC values. J Mater Sci: Mater Med 23:943–953
Astete CE, Sabliov CM (2006) Synthesis and characterization of PLGA nanoparticles. J Biomater Sci Polym Ed 17:247–289
Avgoustakis K, Beletsi A, Panagi Z, Karydas AG, Klepetsanis P, Ithakissios DS (2002) PLGA–mPEG nanoparticles of cisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drug residence in blood properties. J Control Release 79:123–135
Avgoustakis K, Beletsi A, Panagi Z, Klepetsanis P, Livaniou E, Evangelatos G, Ithakissios DS (2003) Effect of copolymer composition on physicochemical characteristics, in vitro stability, and biodistribution of PLGA–mPEG nanoparticles. Int J Pharm 259:115–127
Bazile D, Prud’Homme C, Bassoulet MT, Marlard M, Spenlehauer G, Veillard M (1995) Stealth Me.PEG–PLA nanoparticles avoid uptake by mononuclear phagocytes system. J Pharm Sci 84:493–498
Beletsi A, Leontiadis L, Klepetsanis P, Ithakissios DS, Avgoustakis K (1999) Effect of preparative variables on the properties of poly(dl-lactide-co-glycolide)–methoxypoly(ethyleneglycol) copolymers related to their application in controlled drug delivery. Int J Pharm 182:187–197
Beletsi A, Panagi Z, Avgoustakis K (2005) Biodistribution properties of nanoparticles based on mixtures of PLGA with PLGA–PEG diblock copolymers. Int J Pharm 298:233–241
Benoit JP, Marchais H, Rolland H, Velde VV (1996) Biodegradable microspheres. In: Benita S (ed) Advances in production technology microencapsulation. Methods and industrial applications. Marcel Dekker, New York, pp 36–72
Bouclier C, Moine L, Hillaireau H, Marsaud V, Oplon P, Connault E, Ccouvreur P, Fattal E, Renoir JM (2008) Physicochemical characteristics and preliminary in vivo evaluation of nanocapsules loaded with siRNA targeting estrogen receptor alpha. Biomacromolecules 9:2881–2890
Chen J, Li S, Shen Q, He H, Zhang Y (2011) Enhanced cellular uptake of folic acid-conjugated PLGA–PEG nanoparticles loaded with vincristine sulfate in human breast cancer. Drug Dev Ind Pharm 37:1339–1346
Chen J, Li S, Shen Q (2012) Folic acid and cell-penetrating peptide conjugated PLGA–PEG bifunctional nanoparticles for vincristine sulfate delivery. Eur J Pharm Sci 47:430–443
Cheng J, Teply BA, Sherifi I, Sung J, Luther G, Gu FX, Levy-Nissenbaum E, Radovic-Moreno AF, Langer R, Farokhzad OC (2007) Formulation of functionalized PLGA–PEG nanoparticles for in vivo targeted drug delivery. Biomaterials 28:869–876
Cleveland MV, Flavin DP, Ruben RA, Epstein RM, Clark GE (2001) New polyethylene glycol laxative for treatment of constipation in adults: a randomized, double-blind, placebo-controlled study. South Med J 94:478–481
Comes Franchini M, Bonini BF, Camaggi CM, Gentili D, Pession A, Rani M, Strocchi E (2010a) Design and synthesis of novel pyrazoles for nanomedicine applications against malignant gliomas. Eur J Med Chem 45:2024–2033
Comes Franchini M, Ponti J, Lemor R, Fournelle M, Broggi F, Locatelli E (2010b) Polymeric entrapped thiol-coated gold nanorods: cytotoxicity and suitability as molecular optoacoustic contrast agent. J Mater Chem 20:10908–10914
Danhier F, Lecouturier N, Vroman B, Jérôme C, Marchand-Brynaert J, Feron O, Préat V (2009) Paclitaxel-loaded PEGylated PLGA-based nanoparticles: in vitro and in vivo evaluation. J Control Release 133:11–17
Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ (2008) Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA–PEG nanoparticles. Proc Natl Acad Sci USA 105:17356–17361
Dong Y, Feng S–S (2004) Methoxy poly(ethylene glycol)-poly(lactide) (MPEG–PLA) nanoparticles for controlled delivery of anticancer drugs. Biomaterials 25:2843–2849
Duceppe N, Tabrizian M (2010) Advances in using chitosan-based nanoparticles for in vitro and in vivo drug and gene delivery. Expert Opin Drug Deliv 7:1191–1207
Duncan R, Ringsdorf H, Satchi-Fainaro R (2006) Polymer therapeutics—polymers as drugs, drug and protein conjugates and gene delivery systems: past, present and future opportunities. Adv Polym Sci 192:1–8
Dunn SE, Coombes AGA, Garnett MC, Davis SS, Davies MC, Illum L (1997) In vitro cell interaction and in vivo biodistribution of poly(lactide-co-glycolide) nanospheres surface modified by poloxamer and poloxamine copolymers. J Control Release 44:65–76
Esmaeili F, Ghahremani MH, Ostad SN, Atyabi F, Seydabadi M, Malekshani MR, Amini M, Dinarvand R (2008) Folate-receptor-targeted delivery of docetaxel nanoparticles prepared by PLGA–PEG-folate conjugate. J Drug Target 16:415–423
Farokhzad OC, Cheng J, Teply BA, Sherifi I, Jon S, Kantoff PW, Richie JP, Langer R (2006) Targeted nanoparticle–aptamer bioconjugates for cancer chemotherapy in vivo. Proc Natl Acad Sci USA 103:6315–6320
Feczkò T, Toth J, Gyenis J (2008) Comparison of the preparation of PLGA–BSA nano- and microparticles by PVA, polaxamer and PVP. Colloid Surf A 319:188–195
Feczkò T, Toth J, Dosa G, Gyenis J (2011) Optimization of protein encapsulation in PLGA nanoparticles. Chem Eng Process 50:757–765
Gentili D, Ori G, Comes Franchini M (2009) Double phase transfer of gold nanorods for surface functionalization and entrapment into PEG-based nanocarriers. Chem Comm 39:5874–5876
Ginlding DK, Reed AM (1979) Biodegradable polymers for use in surgery. Polyglycolic/poy(lactic acid) homo- and copolymers. Polymer 20:1459–1464
Graf N, Bielenberg DR, Kolishetti N, Muus C, Banyard J, Farokhzad OC, Lippard SJ (2012) ανβ3 Integrin-Targeted PLGA–PEG nanoparticles for enhanced anti-tumor efficacy of a Pt(IV) prodrug. ACS Nano 6:4530–4539
Greenwald RB, Choe YH, McGuire J, Conover CD (2003) Effective drug delivery by PEGylated drug conjugates. Adv Drug Deliv Rev 55:217–250
Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R (1994) Biodegradable long-circulating polymeric nanospheres. Science 263:1600–1603
Gref R, Domb A, Quellec P, Blunk T, Muller RH, Verbavatz JM, Langer R (1995) The controlled intravenous delivery of drugs using PEG-coated sterically stabilized nanospheres. Adv Drug Deliv Rev 16:215–233
Grobmyer SR, Moudgil BM (2010) Cancer nanotechnology: methods and protocols. Method Mol Biol 624:1–396
Guo J, Gao X, Su L, Xia H, Gu G, Pang Z, Jiang X, Yao L, Chen J, Chen H (2011) Aptamer-functionalized PEG–PLG Ananoparticles for enhanced anti-glioma drug delivery. Biomaterials 32:8010–8020
Hans ML, Lowman AM (2002) Biodegradable nanoparticles for drug delivery and targeting. Curr Opin Solid State Mater Sci 6:319–327
Huh KM, Cho YW, Park K (2003) PLGA–PEG block copolymers for drug formulations. Drug Dev Deliv 3:5
Iwata M, McGinity JW (1992) Preparation of multi-phase microspheres of poly(lactic acid) and poly(lactic-co-glycolic acid) containing a W:O emulsion by a multiple solvent evaporation technique. J Microencapsul 7:201–214
Joralemon MJ, McRae S, Emrick T (2010) PEGylated polymers for medicine: from conjugation to self-assembled systems. Chem Comm 46:1377–1393
Khalil NM, Frabel do Nascimento TC, Casa DM, Dalmolin LF, de Mattos AC, Hoss I, Romano MA, Mainardes RM (2013) Pharmacokinetics of curcumin-loaded PLGA and PLGA–PEG blend nanoparticles after oral administration in rats. Coll Surf B: Biointerfaces 101:353–360
Knop K, Hoogenboom R, Fischer D, Schubert US (2010) Poly(ethylene glycol) in drug delivery: pros and cons as Wellas potential alternatives. Angew Chem Int Ed 49:6288–6308
Kreuter J (1994) Colloidal drug delivery systems. Dekker, New York
Kreuter J (2004) Nanoparticles as drug delivery systems. Encycl Nanosci Nanotechnol 7:161–180
Kumar N, Ravikumarb MVN, Domb AJ (2001) Biodegradable block copolymers. Adv Drug Deliv Rev 53:23–44
Lewis DH (1990) Controlled release of bioactive agents from lactide/glycolide polymers. In: Chasin M, Langer R (eds) Biodegradable polymers as drug delivery systems, drugs and the pharmaceutical sciences. Marcel Dekker, New York, pp 1–41
Li S, McCarthy SP (1999) Influence of crystallinity and stereochemistry on the enzymatic degradation of poly(lactide)s. Macromolecules 32:4454–4456
Li YP, Pei YY, Zhang XY, Gu ZH, Zhou ZH, Yuan WF, Zhou JJ, Zhu JH, Gao XJ (2001) PEGylated PLGA nanoparticles as protein carriers: synthesis preparation and biodistribution in rats. J Control Release 71:203–211
Liang C, Yang Y, Ling Y, Huang Y, Li T, Li X (2011) Improved therapeutic effect of folate-decorated PLGA–PEG nanoparticles for endometrial carcinoma. Bioorganic Med Chem 19:4057–4066
Liu Y, Miyoshi H, Nakamura M (2007) Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles. Int J Cancer 120:2527–2537
Locatelli E, Ori G, Fournelle M, Lemor R, Montorsi M, Comes Franchini M (2011) Click chemistry for the assembly of gold nanorods and silver nanoparticles. Chem Eur J 17:9052–9056
Locatelli E, Broggi F, Ponti J, Marmorato P, Franchini F, Lena S, Comes Franchini M (2012) Lipophilic silver nanoparticles and their polymeric entrapment into targeted-PEG-based micelles for the treatment of glioblastoma. Adv Healthcare Mater 1:342–347
Lu JM, Wang X, Marin-Muller C, Wang H, Lin PH, Yao Q, Chen C (2009) Current advances in research and clinical applications of PLGA-based nanotechnology. Expert Rev Mol Diagn 9:325–341
Luo G, Yu X, Jin C, Yang F, Fu D, Long J, Xu J, Zhan C, Lu W (2010) LyP-1-conjugated nanoparticles for targeting drug delivery to lymphatic metastatic tumors. Int J Pharm 385:150–156
Magenheim B, Benita S (1991) Nanoparticle characterization : a comprehensive physicochemical approach. S.T.P. Pharma Sci 1:221–241
Magenheim B, Levy MY, Benita S (1993) A new in vitro technique for the evaluation of drug release profiles from colloidal carriers-ultrafiltration technique at low pressure. Int J Pharm 94:115–123
McCarron PA, Hall M (2004) Pharmaceutical nanotechnology. Encycl Nanosci Nanotechnol 8:469–487
Mehnert W, Mäder K (2012) Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. doi:10.1016/j.addr.2012.09.021
Moghimi SM, Porter CJH, Muir IS, Illum L, Davis SS (1991) Non phagocytic uptake of intravenously injected microspheres in rat spleen-influence of particles-size and hydrophilic coating. Biochem Biophys Res Commun 177:861–866
Mosqueira VCF, Lengrand P, Morgat JL, Vert M, Mysiakine E, Gref R, Devissaguet JL, Barratt G (2001) Biodistribution of long-circulating PEG-grafted nanocapsules in mice: effects of PEG chain length and density. Pharm Res 18:1411–1419
Muller RH (1991) Colloidal carriers for controlled drug delivery and targeting: modification, characterisation and in vivo distribution. CRC Press, Stuttgart
Muthu MS (2009) Nanoparticles based on PLGA and its co-polymer: an overview. Asian J Pharm 3:266–277
Oh JK (2011) Polylactide (PLA)-based amphiphilic block copolymers: synthesis, self-assembly, and biomedical applications. Soft Matter 7:5096–5108
Oupicky D, Ogris M, Howard KA, Dash PR, Ulbrich K, Seymour LW (2002) Importance of lateral and steric stabilization of polyelectrolyte gene delivery vectors for extended systemic circulation. Mol Ther 5:463–472
Owens DE III, Peppas NA (2006) Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 307:93–102
Park TG (1994) Degradation of poly(d, l-lactic acid) microspheres: effect of molecular weight. J Control Release 30:538–546
Park JH, Lee S, Kim JH, Park K, Kim K, Kwon IC (2008) Polymeric nanomedicine for cancer therapy. Prog Polym Sci 33:113–137
Peracchia MT, Gref R, Minamitake Y, Domb A, Lotan N, Langer R (1997) PEG-coated nanospheres from amphiphilic diblock and multiblock copolymers: investigation of their drug encapsulation and release characteristics. J Control Release 46:23–223
Redhead HM, Davis SS, Illum L (2001) Drug delivery in poly(lactide-co-glycolide) nanoparticles surface modified with poloxamer 407 and poloxamine 908: in vitro characterisation and in vivo evaluation. J Control Release 70:353–363
Schmaljohann D (2006) Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev 58:1655–1670
Schubert S, Delaney JT, Schubert US (2011) Nanoprecipitation and nanoformulation of polymers: from history to powerful possibilities beyond poly(lactic acid). Soft Matter 7:1581–1588
Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE (2001) Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release 70:1–20
Vinagradov SV, Bronich TK, Kabanov AV (2002) Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. Adv Drug Deliv Rev 54:223–233
Vinod Prabhu, Siddik Uzzaman, Berlin Grace VM, Guruvayoorappan C (2011) Nanoparticles in drug delivery and cancer therapy: the giant rats tail. J Cancer Ther 2:325–334
Wanga M, Thanoua M (2010) Targeting nanoparticles to cancer. Pharmacol Res 62:90–99
Washington C (1990) Drug release from micro disperse system. A critical review. Int J Pharm 58:1–12
Win KY, Feng SS (2005) Effects of particle size and surface coating on cellular uptake of polymeric nanoparticles for oral delivery of anticancer drugs. Biomaterials 26:2713–2722
Yoo HS, Park TG (2001) Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA–PEG block copolymer. J Control Release 70:63–70
Yoo HS, Oh JE, Lee KH, Park TG (1999) Biodegradable nanoparticles containing doxorubicin-PLGA conjugate for sustained release. Pharm Res 16:1114–1118
Yu T, Wang YY, Yang M, Schneider C, Zhong W, Pulicare S, Choi WJ, Mert O, Fu J, Lai SK, Hanes J (2012) Biodegradable mucus-penetrating nanoparticles composed of diblock copolymers of polyethylene glycol and poly(lactic-co-glycolic acid). Drug Deliv Transl Res 2:124–128
Zambaux MF, Bonneaux F, Gref R, Maincent P, Dellacherie E, Alonso MJ, Labrude P (1998) Influence of experimental parameters on the characteristic of poly(lactic acid) nanoparticles prepared by a double emulsion method. J Control Release 50:31–40
Zhao H, Yung LYL (2007) Selectivity of folate conjugated polymer micelles against different tumor cells. Int J Pharm 349:256–268
Zimmer A, Kreuter J, Robinson JR (1991) Influence of charged molecules on the zeta potential of PBCA nanoparticles. Proc Int Symp Control Release Bioact Mater 18:642–643
Acknowledgments
This work was supported by the funding of EU-FP7 European project Save Me (contract no. CP-IP 263307-2).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Locatelli, E., Comes Franchini, M. Biodegradable PLGA-b-PEG polymeric nanoparticles: synthesis, properties, and nanomedical applications as drug delivery system. J Nanopart Res 14, 1316 (2012). https://doi.org/10.1007/s11051-012-1316-4
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11051-012-1316-4