Skip to main content
SpringerLink
Log in

PEGylated Pharmaceutical Nanocarriers

  • Chapter
  • First Online:
Long Acting Injections and Implants

Part of the book series: Advances in Delivery Science and Technology ((ADST))

Abstract

Surface coating of various pharmaceutical nanocarriers with polyethylene glycol (PEGylation) is the most popular and elaborated method to prepare drug delivery systems capable of prolonged circulation time in the blood. Prolonged circulation is often required to provide a sufficient time for effective accumulation of drug-loaded nanocarriers in target organs or tissues. This chapter considers key properties of PEG and some other polymers, which can be used to prepare long-circulating nanocarriers, and discusses the most important biological and pharmacological consequences of PEGylation and prolonged circulation. Special attention is paid to the preparation, properties, and application of long-circulating PEGylated liposomes, a popular and clinically approved drug delivery system. PEGylated polymeric nanoparticles, iron oxide nanoparticles, dendrimers, and other pharmaceutical nanocarriers are also described. The combination of longevity and specific targeting ability (attachment of both protecting polymer and targeting ligand to the surface of nanocarriers) is discussed as the next step in the development of effective drug delivery systems.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Alonso MJ (2004) Nanomedicines for overcoming biological barriers. Biomed Pharmacother 58:168–172

    Article  PubMed  CAS  Google Scholar 

  2. Gregoriadis G (1988) Liposomes as drug carriers: recent trends and progress. Wiley, New York, p 910

    Google Scholar 

  3. Müller RH (1991) Colloidal carriers for controlled drug delivery and targeting: modification, characterization, and in vivo distribution. Wissenschaftliche Verlagsgesellschaft/CRC, Stuttgart/Boca Raton, FL

    Google Scholar 

  4. Rolland A (1993) Pharmaceutical particulate carriers: therapeutic applications carriers. Marcel Dekker, New York

    Google Scholar 

  5. Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP, Jain RK (1995) Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752–3756

    PubMed  CAS  Google Scholar 

  6. Torchilin VP (1998) Polymer-coated long-circulating microparticulate pharmaceuticals. J Microencapsul 15:1–19

    Article  PubMed  CAS  Google Scholar 

  7. Torchilin VP (2001) Structure and design of polymeric surfactant-based drug delivery systems. J Control Release 73:137–172

    Article  PubMed  CAS  Google Scholar 

  8. Cohen S, Bernstein H (1996) Microparticulate systems for the delivery of proteins and vaccines. Dekker, New York

    Google Scholar 

  9. Lasic DD, Martin FJ (1995) Stealth liposomes. CRC, Boca Raton, FL, p 320

    Google Scholar 

  10. Moghimi SM, Szebeni J (2003) Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties. Prog Lipid Res 42:463–478

    Article  PubMed  CAS  Google Scholar 

  11. Torchilin VP (1996) How do polymers prolong circulation times of liposomes. J Liposome Res 9:99–116

    Article  Google Scholar 

  12. Torchilin VP, Trubetskoy VS (1995) Which polymers can make nanoparticulate drug carriers long-circulating? Adv Drug Deliv Rev 16:141–155

    Article  CAS  Google Scholar 

  13. Winslow RM, Vandegriff KD, Intaglietta M (1996) Blood substitutes: new challenges. Birkhäuser, Boston, MA

    Book  Google Scholar 

  14. Gabizon AA (1995) Liposome circulation time and tumor targeting: implications for cancer chemotherapy. Adv Drug Deliv Rev 16:285–294

    Article  CAS  Google Scholar 

  15. Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv Enzyme Regul 41:189–207

    Article  PubMed  CAS  Google Scholar 

  16. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271–284

    Article  PubMed  CAS  Google Scholar 

  17. Kommareddy S, Tiwari SB, Amiji MM (2005) Long-circulating polymeric nanovectors for tumor-selective gene delivery. Technol Cancer Res Treat 4:615–625

    PubMed  CAS  Google Scholar 

  18. Molyneux P (1984) Water-soluble synthetic polymers: properties and behavior. CRC, Boca Raton, FL

    Google Scholar 

  19. Napper DH (1983) Polymeric stabilization of colloidal dispersions. Academic, London

    Google Scholar 

  20. Allen TM, Hansen C, Martin F, Redemann C, Yau-Young A (1991) Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. Biochim Biophys Acta 1066:29–36

    Article  PubMed  CAS  Google Scholar 

  21. Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268:235–237

    Article  PubMed  CAS  Google Scholar 

  22. Maruyama K, Yuda T, Okamoto A, Ishikura C, Kojima S, Iwatsuru M (1991) Effect of molecular weight in amphipathic polyethyleneglycol on prolonging the circulation time of large unilamellar liposomes. Chem Pharm Bull (Tokyo) 39:1620–1622

    Article  CAS  Google Scholar 

  23. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, Lee KD, Woodle MC, Lasic DD, Redemann C et al (1991) Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 88:11460–11464

    Article  PubMed  CAS  Google Scholar 

  24. Senior J, Delgado C, Fisher D, Tilcock C, Gregoriadis G (1991) Influence of surface hydrophilicity of liposomes on their interaction with plasma protein and clearance from the circulation: studies with poly(ethylene glycol)-coated vesicles. Biochim Biophys Acta 1062:77–82

    Article  PubMed  CAS  Google Scholar 

  25. Gabizon A, Papahadjopoulos D (1992) The role of surface charge and hydrophilic groups on liposome clearance in vivo. Biochim Biophys Acta 1103:94–100

    Article  PubMed  CAS  Google Scholar 

  26. Lasic DD, Martin FJ, Gabizon A, Huang SK, Papahadjopoulos D (1991) Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim Biophys Acta 1070:187–192

    Article  PubMed  CAS  Google Scholar 

  27. Torchilin VP, Omelyanenko VG, Papisov MI, Bogdanov AA Jr, Trubetskoy VS, Herron JN, Gentry CA (1994) Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity. Biochim Biophys Acta 1195:11–20

    Article  PubMed  CAS  Google Scholar 

  28. Torchilin VP, Papisov MI (1994) Why do polyethylene glycol-coated liposomes circulate so long? J Liposome Res 4:725–739

    Article  Google Scholar 

  29. Senior JH (1987) Fate and behavior of liposomes in vivo: a review of controlling factors. Crit Rev Ther Drug Carrier Syst 3:123–193

    PubMed  CAS  Google Scholar 

  30. Needham D, McIntosh TJ, Lasic DD (1992) Repulsive interactions and mechanical stability of polymer-grafted lipid membranes. Biochim Biophys Acta 1108:40–48

    Article  PubMed  CAS  Google Scholar 

  31. Pang SNJ (1993) Final report on the safety assessment of Polyethylene glycols (PEGs) -6, -8, -32, -75, -150, -14M, -20M. J Am Coll Toxicol 12:429–457

    Article  Google Scholar 

  32. Powell GM (1980) Polyethylene glycol. In: Davidson RL (ed) Handbook of water-soluble gums and resins. McGraw-Hill, New York, pp 1–31

    Google Scholar 

  33. Yamaoka T, Tabata Y, Ikada Y (1994) Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci 83:601–606

    Article  PubMed  CAS  Google Scholar 

  34. Zalipsky S (1995) Chemistry of polyethylene glycol conjugates with biologically active molecules. Adv Drug Deliv Rev 16:157–182

    Article  CAS  Google Scholar 

  35. Torchilin VP (2002) Strategies and means for drug targeting: an overview. In: Muzykantov V, Torchilin VP (eds) Biomedical aspects of drug targeting. Kluwer, Boston, MA, pp 3–26

    Google Scholar 

  36. Veronese FM (2001) Peptide and protein PEGylation: a review of problems and solutions. Biomaterials 22:405–417

    Article  PubMed  CAS  Google Scholar 

  37. Torchilin VP, Levchenko TS, Whiteman KR, Yaroslavov AA, Tsatsakis AM, Rizos AK, Michailova EV, Shtilman MI (2001) Amphiphilic poly-N-vinylpyrrolidones: synthesis, properties and liposome surface modification. Biomaterials 22:3035–3044

    Article  PubMed  CAS  Google Scholar 

  38. Torchilin VP, Shtilman MI, Trubetskoy VS, Whiteman K, Milstein AM (1994) Amphiphilic vinyl polymers effectively prolong liposome circulation time in vivo. Biochim Biophys Acta 1195:181–184

    Article  PubMed  CAS  Google Scholar 

  39. Wood C, Kabat EA (1981) Immunochemical studies of conjugates of isomaltosyl oligosaccharides to lipid. I. Antigenicity of the glycolipids and the production of specific antibodies in rabbits. J Exp Med 154:432–449

    Article  PubMed  CAS  Google Scholar 

  40. Des Cloizeaux J, Jannink G (1990) Polymers in solution: their modelling and structure. Clarendon Press/Oxford University Press, Oxford/New York

    Google Scholar 

  41. Torchilin VP, Trubetskoy VS, Whiteman KR, Caliceti P, Ferruti P, Veronese FM (1995) New synthetic amphiphilic polymers for steric protection of liposomes in vivo. J Pharm Sci 84:1049–1053

    Article  PubMed  CAS  Google Scholar 

  42. Monfardini C, Schiavon O, Caliceti P, Morpurgo M, Harris JM, Veronese FM (1995) A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjug Chem 6:62–69

    Article  PubMed  CAS  Google Scholar 

  43. Ranucci E, Spagnoli G, Sartore L, Ferutti P (1994) Synthesis and molecular weight characterization of low molecular weight end-functionalized poly(4-acryloymorpholine). Macromol Chem Phys 195:3469–3479

    Article  CAS  Google Scholar 

  44. Sartore L, Ranucci E, Ferutti P, Caliceti P, Schiavon O, Veronese FM (1994) Low molecular weight end-functionalized poly(N-vinylpyrrolidone) for the modifications of polypeptide aminogroups. J Bioact Compact Polym 9:411–427

    Article  CAS  Google Scholar 

  45. Torchilin VP, Trubetskoy VS, Milshteyn AM, Canillo J, Wolf GL, Papisov MI, Bogdanov AA, Narula J, Khaw BA, Omelyanenko VG (1994) Targeted delivery of diagnostic agents by surface-modified liposomes. J Control Release 28:45–58

    Article  CAS  Google Scholar 

  46. Torchilin VP, Trubetskoy VS, Papisov MI, Bogdanov AA, Omelyanenko VG, Narula J, Khaw BA (1993) Polymer-coated immunoliposomes for delivery of pharmaceuticals: targeting and biological stability. In: 20th international symposium on controlled release of bioactive materials. Controlled Release Society, Washington, pp 194–195

    Google Scholar 

  47. Woodle MC, Engbers CM, Zalipsky S (1994) New amphipatic polymer-lipid conjugates forming long-circulating reticuloendothelial system-evading liposomes. Bioconjug Chem 5:493–496

    Article  PubMed  CAS  Google Scholar 

  48. Maruyama K, Okuizumi S, Ishida O, Yamauchi H, Kikuchi H, Iwatsuru M (1994) Phosphatidyl polyglycerols prolong liposome circulation in vivo. Int J Pharm 111:103–107

    Article  CAS  Google Scholar 

  49. Takeuchi H, Kojima H, Toyoda T, Yamamoto H, Hino T, Kawashima Y (1999) Prolonged circulation time of doxorubicin-loaded liposomes coated with a modified polyvinyl alcohol after intravenous injection in rats. Eur J Pharm Biopharm 48:123–129

    Article  PubMed  CAS  Google Scholar 

  50. Klibanov AL, Maruyama K, Beckerleg AM, Torchilin VP, Huang L (1991) Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim Biophys Acta 1062:142–148

    Article  PubMed  CAS  Google Scholar 

  51. Maruyama K, Takizawa T, Yuda T, Kennel SJ, Huang L, Iwatsuru M (1995) Targetability of novel immunoliposomes modified with amphipathic poly(ethylene glycol)s conjugated at their distal terminals to monoclonal antibodies. Biochim Biophys Acta 1234:74–80

    Article  PubMed  Google Scholar 

  52. Gregoriadis G (1993) Liposome technology, 2nd edn. CRC, Boca Raton, FL

    Google Scholar 

  53. Lasic DD, Barenholz Y (1996) Handbook of nonmedical applications of liposomes. CRC, Boca Raton, FL

    Google Scholar 

  54. Sou K, Endo T, Takeoka S, Tsuchida E (2000) Poly(ethylene glycol)-modification of the phospholipid vesicles by using the spontaneous incorporation of poly(ethylene glycol)-lipid into the vesicles. Bioconjug Chem 11:372–379

    Article  PubMed  CAS  Google Scholar 

  55. Gabizon A, Papahadjopoulos D (1988) Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 85:6949–6953

    Article  PubMed  CAS  Google Scholar 

  56. Allen TM, Mehra T, Hansen C, Chin YC (1992) Stealth liposomes: an improved sustained release system for 1-beta-d-arabinofuranosylcytosine. Cancer Res 52:2431–2439

    PubMed  CAS  Google Scholar 

  57. Boman NL, Masin D, Mayer LD, Cullis PR, Bally MB (1994) Liposomal vincristine which exhibits increased drug retention and increased circulation longevity cures mice bearing P388 tumors. Cancer Res 54:2830–2833

    PubMed  CAS  Google Scholar 

  58. Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R, Martin F, Huang A, Barenholz Y (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54:987–992

    PubMed  CAS  Google Scholar 

  59. Huang SK, Stauffer PR, Hong K, Guo JW, Phillips TL, Huang A, Papahadjopoulos D (1994) Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes. Cancer Res 54:2186–2191

    PubMed  CAS  Google Scholar 

  60. Ewer MS, Martin FJ, Henderson C, Shapiro CL, Benjamin RS, Gabizon AA (2004) Cardiac safety of liposomal anthracyclines. Semin Oncol 31:161–181

    Article  PubMed  CAS  Google Scholar 

  61. Rose PG (2005) Pegylated liposomal doxorubicin: optimizing the dosing schedule in ovarian cancer. Oncologist 10:205–214

    Article  PubMed  CAS  Google Scholar 

  62. Allen TM, Hansen CB, de Menezes DEL (1995) Pharmacokinetics of long-circulating liposomes. Adv Drug Deliv Rev 16:267–284

    Article  CAS  Google Scholar 

  63. Hwang KJ (1987) Liposome pharmacokinetics. In: Ostro MJ (ed) Liposomes: from biophysics to therapeutics. Dekker, New York, pp 109–156

    Google Scholar 

  64. Allen TM, Hansen C (1991) Pharmacokinetics of stealth versus conventional liposomes: effect of dose. Biochim Biophys Acta 1068:133–141

    Article  PubMed  CAS  Google Scholar 

  65. Huang SK, Mayhew E, Gilani S, Lasic DD, Martin FJ, Papahadjopoulos D (1992) Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma. Cancer Res 52:6774–6781

    PubMed  CAS  Google Scholar 

  66. Mayhew EG, Lasic D, Babbar S, Martin FJ (1992) Pharmacokinetics and antitumor activity of epirubicin encapsulated in long-circulating liposomes incorporating a polyethylene glycol-derivatized phospholipid. Int J Cancer 51:302–309

    Article  PubMed  CAS  Google Scholar 

  67. Allen TM, Hansen C, Rutledge J (1989) Liposomes with prolonged circulation times: factors affecting uptake by reticuloendothelial and other tissues. Biochim Biophys Acta 981:27–35

    Article  PubMed  CAS  Google Scholar 

  68. Liu D, Mori A, Huang L (1991) Large liposomes containing ganglioside GM1 accumulate effectively in spleen. Biochim Biophys Acta 1066:159–165

    Article  PubMed  CAS  Google Scholar 

  69. Liu D, Mori A, Huang L (1992) Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. Biochim Biophys Acta 1104:95–101

    Article  PubMed  CAS  Google Scholar 

  70. Maruyama K, Yuda T, Okamoto A, Kojima S, Suginaka A, Iwatsuru M (1992) Prolonged circulation time in vivo of large unilamellar liposomes composed of distearoyl phosphatidylcholine and cholesterol containing amphipathic poly(ethylene glycol). Biochim Biophys Acta 1128:44–49

    PubMed  CAS  Google Scholar 

  71. Guo X, Szoka FC Jr (2001) Steric stabilization of fusogenic liposomes by a low-pH sensitive PEG-diortho ester-lipid conjugate. Bioconjug Chem 12:291–300

    Article  PubMed  CAS  Google Scholar 

  72. Boomer JA, Thompson DH (1999) Synthesis of acid-labile diplasmenyl lipids for drug and gene delivery applications. Chem Phys Lipids 99:145–153

    Article  PubMed  CAS  Google Scholar 

  73. Zalipsky S, Qazen M, Walker JA II, Mullah N, Quinn YP, Huang SK (1999) New detachable poly(ethylene glycol) conjugates: cysteine-cleavable lipopolymers regenerating natural phospholipid, diacyl phosphatidylethanolamine. Bioconjug Chem 10:703–707

    Article  PubMed  CAS  Google Scholar 

  74. Roux E, Francis M, Winnik FM, Leroux JC (2002) Polymer based pH-sensitive carriers as a means to improve the cytoplasmic delivery of drugs. Int J Pharm 242:25–36

    Article  PubMed  CAS  Google Scholar 

  75. Roux E, Passirani C, Scheffold S, Benoit JP, Leroux JC (2004) Serum-stable and long-circulating, PEGylated, pH-sensitive liposomes. J Control Release 94:447–451

    Article  PubMed  CAS  Google Scholar 

  76. Simoes S, Moreira JN, Fonseca C, Duzgunes N, de Lima MC (2004) On the formulation of pH-sensitive liposomes with long circulation times. Adv Drug Deliv Rev 56:947–965

    Article  PubMed  CAS  Google Scholar 

  77. Kratz F, Beyer U, Schutte MT (1999) Drug-polymer conjugates containing acid-cleavable bonds. Crit Rev Ther Drug Carrier Syst 16:245–288

    PubMed  CAS  Google Scholar 

  78. Zhang JX, Zalipsky S, Mullah N, Pechar M, Allen TM (2004) Pharmaco attributes of dioleoylphosphatidylethanolamine/cholesterylhemisuccinate liposomes containing different types of cleavable lipopolymers. Pharmacol Res 49:185–198

    Article  PubMed  CAS  Google Scholar 

  79. Leroux J, Roux E, Le Garrec D, Hong K, Drummond DC (2001) N-isopropylacrylamide copolymers for the preparation of pH-sensitive liposomes and polymeric micelles. J Control Release 72:71–84

    Article  PubMed  CAS  Google Scholar 

  80. Roux E, Stomp R, Giasson S, Pezolet M, Moreau P, Leroux JC (2002) Steric stabilization of liposomes by pH-responsive N-isopropylacrylamide copolymer. J Pharm Sci 91:1795–1802

    Article  PubMed  CAS  Google Scholar 

  81. Lee ES, Na K, Bae YH (2003) Polymeric micelle for tumor pH and folate-mediated targeting. J Control Release 91:103–113

    Article  PubMed  CAS  Google Scholar 

  82. Lee ES, Shin HJ, Na K, Bae YH (2003) Poly(l-histidine)-PEG block copolymer micelles and pH-induced destabilization. J Control Release 90:363–374

    Article  PubMed  CAS  Google Scholar 

  83. Sudimack JJ, Guo W, Tjarks W, Lee RJ (2002) A novel pH-sensitive liposome formulation containing oleyl alcohol. Biochim Biophys Acta 1564:31–37

    Article  PubMed  CAS  Google Scholar 

  84. Jones MC, Ranger M, Leroux JC (2003) pH-sensitive unimolecular polymeric micelles: synthesis of a novel drug carrier. Bioconjug Chem 14:774–781

    Article  PubMed  CAS  Google Scholar 

  85. Suzawa T, Nagamura S, Saito H, Ohta S, Hanai N, Kanazawa J, Okabe M, Yamasaki M (2002) Enhanced tumor cell selectivity of adriamycin-monoclonal antibody conjugate via a poly(ethylene glycol)-based cleavable linker. J Control Release 79:229–242

    Article  PubMed  CAS  Google Scholar 

  86. Potineni A, Lynn DM, Langer R, Amiji MM (2003) Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive biodegradable system for paclitaxel delivery. J Control Release 86:223–234

    Article  PubMed  CAS  Google Scholar 

  87. Cheung CY, Murthy N, Stayton PS, Hoffman AS (2001) A pH-sensitive polymer that enhances cationic lipid-mediated gene transfer. Bioconjug Chem 12:906–910

    Article  PubMed  CAS  Google Scholar 

  88. Venugopalan P, Jain S, Sankar S, Singh P, Rawat A, Vyas SP (2002) pH-sensitive liposomes: mechanism of triggered release to drug and gene delivery prospects. Pharmazie 57:659–671

    PubMed  CAS  Google Scholar 

  89. Yoo HS, Lee EA, Park TG (2002) Doxorubicin-conjugated biodegradable polymeric micelles having acid-cleavable linkages. J Control Release 82:17–27

    Article  PubMed  CAS  Google Scholar 

  90. Li C, Cui J, Wang C, Wang J, Li Y, Zhang L, Guo W, Wang Y (2008) Lipid composition and grafted PEG affect in vivo activity of liposomal mitoxantrone. Int J Pharm 362:60–66

    Article  PubMed  CAS  Google Scholar 

  91. Maeda H, Sawa T, Konno T (2001) Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS. J Control Release 74:47–61

    Article  PubMed  CAS  Google Scholar 

  92. Sadzuka Y, Kishi K, Hirota S, Sonobe T (2003) Effect of polyethyleneglycol (PEG) chain on cell uptake of PEG-modified liposomes. J Liposome Res 13:157–172

    Article  PubMed  CAS  Google Scholar 

  93. Immordino ML, Dosio F, Cattel L (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomed 1:297–315

    Article  CAS  Google Scholar 

  94. Ogawara K, Un K, Minato K, Tanaka K, Higaki K, Kimura T (2008) Determinants for in vivo anti-tumor effects of PEG liposomal doxorubicin: importance of vascular permeability within tumors. Int J Pharm 359:234–240

    Article  PubMed  CAS  Google Scholar 

  95. Centis V, Vermette P (2008) Physico-chemical properties and cytotoxicity assessment of PEG-modified liposomes containing human hemoglobin. Colloids Surf B Biointerfaces 65:239–246

    Article  PubMed  CAS  Google Scholar 

  96. Taguchi K, Urata Y, Anraku M, Watanabe H, Kadowaki D, Sakai H, Horinouchi H, Kobayashi K, Tsuchida E, Maruyama T, Otagiri M (2009) Hemoglobin vesicles, polyethylene glycol (PEG)ylated liposomes developed as a red blood cell substitute, do not induce the accelerated blood clearance phenomenon in mice. Drug Metab Dispos 37:2197–2203

    Article  PubMed  CAS  Google Scholar 

  97. Jung SH, Seong H, Cho SH, Jeong KS, Shin BC (2009) Polyethylene glycol-complexed cationic liposome for enhanced cellular uptake and anticancer activity. Int J Pharm 382:254–261

    Article  PubMed  CAS  Google Scholar 

  98. Kim JY, Kim JK, Park JS, Byun Y, Kim CK (2009) The use of PEGylated liposomes to prolong circulation lifetimes of tissue plasminogen activator. Biomaterials 30:5751–5756

    Article  PubMed  CAS  Google Scholar 

  99. Auguste DT, Furman K, Wong A, Fuller J, Armes SP, Deming TJ, Langer R (2008) Triggered release of siRNA from poly(ethylene glycol)-protected, pH-dependent liposomes. J Control Release 130:266–274

    Article  PubMed  CAS  Google Scholar 

  100. Negishi Y, Endo Y, Fukuyama T, Suzuki R, Takizawa T, Omata D, Maruyama K, Aramaki Y (2008) Delivery of siRNA into the cytoplasm by liposomal bubbles and ultrasound. J Control Release 132:124–130

    Article  PubMed  CAS  Google Scholar 

  101. Suzuki R, Takizawa T, Negishi Y, Utoguchi N, Maruyama K (2007) Effective gene delivery with liposomal bubbles and ultrasound as novel non-viral system. J Drug Target 15:531–537

    Article  PubMed  CAS  Google Scholar 

  102. Suzuki R, Takizawa T, Negishi Y, Utoguchi N, Maruyama K (2008) Effective gene delivery with novel liposomal bubbles and ultrasonic destruction technology. Int J Pharm 354:49–55

    Article  PubMed  CAS  Google Scholar 

  103. Suzuki R, Yamada Y, Harashima H (2007) Efficient cytoplasmic protein delivery by means of a multifunctional envelope-type nano device. Biol Pharm Bull 30:758–762

    Article  PubMed  CAS  Google Scholar 

  104. Vali AM, Toliyat T, Shafaghi B, Dadashzadeh S (2008) Preparation, optimization, and characterization of topotecan loaded PEGylated liposomes using factorial design. Drug Dev Ind Pharm 34:10–23

    Article  PubMed  CAS  Google Scholar 

  105. Dadashzadeh S, Vali AM, Rezaie M (2008) The effect of PEG coating on in vitro cytotoxicity and in vivo disposition of topotecan loaded liposomes in rats. Int J Pharm 353:251–259

    Article  PubMed  CAS  Google Scholar 

  106. Kale AA, Torchilin VP (2007) Enhanced transfection of tumor cells in vivo using “Smart” pH-sensitive TAT-modified pegylated liposomes. J Drug Target 15:538–545

    Article  PubMed  CAS  Google Scholar 

  107. Kale AA, Torchilin VP (2007) “Smart” drug carriers: PEGylated TATp-modified pH-sensitive liposomes. J Liposome Res 17:197–203

    Article  PubMed  CAS  Google Scholar 

  108. Xu H, Deng Y, Chen D, Hong W, Lu Y, Dong X (2008) Esterase-catalyzed dePEGylation of pH-sensitive vesicles modified with cleavable PEG-lipid derivatives. J Control Release 130:238–245

    Article  PubMed  CAS  Google Scholar 

  109. Ishida T, Kashima S, Kiwada H (2008) The contribution of phagocytic activity of liver macrophages to the accelerated blood clearance (ABC) phenomenon of PEGylated liposomes in rats. J Control Release 126:162–165

    Article  PubMed  CAS  Google Scholar 

  110. Ishida T, Kiwada H (2008) Accelerated blood clearance (ABC) phenomenon upon repeated injection of PEGylated liposomes. Int J Pharm 354:56–62

    Article  PubMed  CAS  Google Scholar 

  111. Bala I, Hariharan S, Kumar MN (2004) PLGA nanoparticles in drug delivery: the state of the art. Crit Rev Ther Drug Carrier Syst 21:387–422

    Article  PubMed  CAS  Google Scholar 

  112. Coombes AG, Tasker S, Lindblad M, Holmgren J, Hoste K, Toncheva V, Schacht E, Davies MC, Illum L, Davis SS (1997) Biodegradable polymeric microparticles for drug delivery and vaccine formulation: the surface attachment of hydrophilic species using the concept of poly(ethylene glycol) anchoring segments. Biomaterials 18:1153–1161

    Article  PubMed  CAS  Google Scholar 

  113. Moghimi SM (1995) Mechanisms regulating body distribution of nanospheres conditioned with pluronic and tetronic block co-polymers. Adv Drug Deliv Rev 16:183–193

    Article  CAS  Google Scholar 

  114. Moghimi SM, Hunter AC (2001) Capture of stealth nanoparticles by the body’s defences. Crit Rev Ther Drug Carrier Syst 18:527–550

    PubMed  CAS  Google Scholar 

  115. Moghimi SM, Hunter AC, Murray JC (2001) Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev 53:283–318

    PubMed  CAS  Google Scholar 

  116. Stolnik S, Illum L, Davis SS (1995) Long circulating microparticulate drug carriers. Adv Drug Deliv Rev 16:195–214

    Article  CAS  Google Scholar 

  117. Moghimi SM, Porter CJH, Illum L, Davis SS (1991) The effect of Poloxamer-407 on liposome stability and targeting to bone marrow: comparison with polystyrene microspheres. Int J Pharm 68:121–126

    Article  CAS  Google Scholar 

  118. Illum SL, Davis SS (1983) Effect of the nonionic surfactant Poloxamer 338 on the fate and deposition of polystyrene microspheres following intravenous administration. J Pharm Sci 72:1086–1089

    Article  PubMed  CAS  Google Scholar 

  119. Moghimi SM, Hawley AE, Christy NM, Gray T, Illum L, Davis SS (1994) Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes. FEBS Lett 344:25–30

    Article  PubMed  CAS  Google Scholar 

  120. Patel HM, Moghimi S (1990) Tissue specific opsonins and phagocytosis of liposomes. In: Gregoriadis G, Allison AC, Poste G (eds) Targeting of drugs 2: optimization strategies. Plenum, New York, p 87

    Google Scholar 

  121. Porter CJ, Moghimi SM, Illum L, Davis SS (1992) The polyoxyethylene/polyoxypropylene block co-polymer Poloxamer-407 selectively redirects intravenously injected microspheres to sinusoidal endothelial cells of rabbit bone marrow. FEBS Lett 305:62–66

    Article  PubMed  CAS  Google Scholar 

  122. Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R (1994) Biodegradable long-circulating polymeric nanospheres. Science 263:1600–1603

    Article  PubMed  CAS  Google Scholar 

  123. Harper GR, Davies MC, Davis SS, Tadros TF, Taylor DC, Irving MP, Waters JA (1991) Steric stabilization of microspheres with grafted polyethylene oxide reduces phagocytosis by rat Kupffer cells in vitro. Biomaterials 12:695–700

    Article  PubMed  CAS  Google Scholar 

  124. Muller M, Voros J, Csucs G, Walter E, Danuser G, Merkle HP, Spencer ND, Textor M (2003) Surface modification of PLGA microspheres. J Biomed Mater Res A 66:55–61

    Article  PubMed  CAS  Google Scholar 

  125. Calvo P, Gouritin B, Chacun H, Desmaele D, D’Angelo J, Noel JP, Georgin D, Fattal E, Andreux JP, Couvreur P (2001) Long-circulating PEGylated polycyanoacrylate nanoparticles as new drug carrier for brain delivery. Pharm Res 18:1157–1166

    Article  PubMed  CAS  Google Scholar 

  126. Peracchia MT, Fattal E, Desmaele D, Besnard M, Noel JP, Gomis JM, Appel M, d’Angelo J, Couvreur P (1999) Stealth PEGylated polycyanoacrylate nanoparticles for intravenous administration and splenic targeting. J Control Release 60:121–128

    Article  PubMed  CAS  Google Scholar 

  127. Bhadra D, Bhadra S, Jain S, Jain NK (2003) A PEGylated dendritic nanoparticulate carrier of fluorouracil. Int J Pharm 257:111–124

    Article  PubMed  CAS  Google Scholar 

  128. De Campos AM, Sanchez A, Gref R, Calvo P, Alonso MJ (2003) The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa. Eur J Pharm Sci 20:73–81

    Article  PubMed  CAS  Google Scholar 

  129. Allen TM (1994) The use of glycolipids and hydrophilic polymers in avoiding rapid uptake of liposomes by the mononuclear phagocyte system. Adv Drug Deliv Rev 13:285–309

    Article  CAS  Google Scholar 

  130. Jamshaid M, Farr SJ, Kearney P, Kellaway IW (1988) Poloxamer sorption on liposomes: comparison with polystyrene latex and influence on solute efflux. Int J Pharm 48:125–131

    Article  CAS  Google Scholar 

  131. Woodle MC, Newman MS, Martin FJ (1992) Liposome leakage and blood circulation: comparison of absorbed block copolymers with covalent attachment of PEG. Int J Pharm 88:327–334

    Article  CAS  Google Scholar 

  132. Gaucher G, Asahina K, Wang J, Leroux JC (2009) Effect of poly(N-vinyl-pyrrolidone)-block-poly(d,l-lactide) as coating agent on the opsonization, phagocytosis, and pharmacokinetics of biodegradable nanoparticles. Biomacromolecules 10:408–416

    Article  PubMed  CAS  Google Scholar 

  133. Besheer A, Vogel J, Glanz D, Kressler J, Groth T, Mader K (2009) Characterization of PLGA nanospheres stabilized with amphiphilic polymers: hydrophobically modified hydroxyethyl starch vs pluronics. Mol Pharm 6:407–415

    Article  PubMed  CAS  Google Scholar 

  134. Shan X, Yuan Y, Liu C, Tao X, Sheng Y, Xu F (2009) Influence of PEG chain on the complement activation suppression and longevity in vivo prolongation of the PCL biomedical nanoparticles. Biomed Microdevices 11:1187–1194

    Article  PubMed  CAS  Google Scholar 

  135. Gindy ME, Ji S, Hoye TR, Panagiotopoulos AZ, Prud’homme RK (2008) Preparation of poly(ethylene glycol) protected nanoparticles with variable bioconjugate ligand density. Biomacromolecules 9:2705–2711

    Article  PubMed  CAS  Google Scholar 

  136. Betancourt T, Byrne JD, Sunaryo N, Crowder SW, Kadapakkam M, Patel S, Casciato S, Brannon-Peppas L (2009) PEGylation strategies for active targeting of PLA/PLGA nanoparticles. J Biomed Mater Res A 91:263–276

    PubMed  Google Scholar 

  137. Cu Y, Saltzman WM (2009) Controlled surface modification with poly(ethylene)glycol enhances diffusion of PLGA nanoparticles in human cervical mucus. Mol Pharm 6:173–181

    Article  PubMed  CAS  Google Scholar 

  138. Chan JM, Zhang L, Yuet KP, Liao G, Rhee JW, Langer R, Farokhzad OC (2009) PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery. Biomaterials 30:1627–1634

    Article  PubMed  CAS  Google Scholar 

  139. Shin SB, Cho HY, Kim DD, Choi HG, Lee YB (2009) Preparation and evaluation of tacrolimus-loaded nanoparticles for lymphatic delivery. Eur J Pharm Biopharm 74(2):164–171

    Article  PubMed  CAS  Google Scholar 

  140. Li R, Li X, Xie L, Ding D, Hu Y, Qian X, Yu L, Ding Y, Jiang X, Liu B (2009) Preparation and evaluation of PEG-PCL nanoparticles for local tetradrine delivery. Int J Pharm 379:158–166

    Article  PubMed  CAS  Google Scholar 

  141. Gou M, Zheng L, Peng X, Men K, Zheng X, Zeng S, Guo G, Luo F, Zhao X, Chen L, Wei Y, Qian Z (2009) Poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL) nanoparticles for honokiol delivery in vitro. Int J Pharm 375:170–176

    Article  PubMed  CAS  Google Scholar 

  142. Ishihara T, Kubota T, Choi T, Higaki M (2009) Treatment of experimental arthritis with stealth-type polymeric nanoparticles encapsulating betamethasone phosphate. J Pharmacol Exp Ther 329:412–417

    Article  PubMed  CAS  Google Scholar 

  143. Davaran S, Rashidi MR, Pourabbas B, Dadashzadeh M, Haghshenas NM (2006) Adriamycin release from poly(lactide-coglycolide)-polyethylene glycol nanoparticles: synthesis, and in vitro characterization. Int J Nanomed 1:535–539

    Article  CAS  Google Scholar 

  144. Zhang X, Zhang H, Wu Z, Wang Z, Niu H, Li C (2008) Nasal absorption enhancement of insulin using PEG-grafted chitosan nanoparticles. Eur J Pharm Biopharm 68:526–534

    Article  PubMed  CAS  Google Scholar 

  145. Zhang XG, Teng DY, Wu ZM, Wang X, Wang Z, Yu DM, Li CX (2008) PEG-grafted chitosan nanoparticles as an injectable carrier for sustained protein release. J Mater Sci Mater Med 19:3525–3533

    Article  PubMed  CAS  Google Scholar 

  146. Gupta AK, Gupta M (2005) Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26:3995–4021

    Article  PubMed  CAS  Google Scholar 

  147. Illum L, Church AE, Butterworth MD, Arien A, Whetstone J, Davis SS (2001) Development of systems for targeting the regional lymph nodes for diagnostic imaging: in vivo behaviour of colloidal PEG-coated magnetite nanospheres in the rat following interstitial administration. Pharm Res 18:640–645

    Article  PubMed  CAS  Google Scholar 

  148. Gupta AK, Curtis AS (2004) Surface modified superparamagnetic nanoparticles for drug delivery: interaction studies with human fibroblasts in culture. J Mater Sci Mater Med 15:493–496

    Article  PubMed  CAS  Google Scholar 

  149. Amstad E, Zurcher S, Mashaghi A, Wong JY, Textor M, Reimhult E (2009) Surface functionalization of single superparamagnetic iron oxide nanoparticles for targeted magnetic resonance imaging. Small 5:1334–1342

    Article  PubMed  CAS  Google Scholar 

  150. Barrera C, Herrera AP, Rinaldi C (2009) Colloidal dispersions of monodisperse magnetite nanoparticles modified with poly(ethylene glycol). J Colloid Interface Sci 329:107–113

    Article  PubMed  CAS  Google Scholar 

  151. Sawant RM, Sawant RR, Gultepe E, Nagesha D, Papahadjopoulos-Sternberg B, Sridhar S, Torchilin VP (2009) Nanosized cancer cell-targeted polymeric immunomicelles loaded with supermagnetic iron oxide nanoparticles. J Nanopart Res 11:1777–1785

    Article  CAS  Google Scholar 

  152. Gou ML, Qian ZY, Wang H, Tang YB, Huang MJ, Kan B, Wen YJ, Dai M, Li XY, Gong CY, Tu MJ (2008) Preparation and characterization of magnetic poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) microspheres. J Mater Sci Mater Med 19:1033–1041

    Article  PubMed  CAS  Google Scholar 

  153. Zhang F, Kang ET, Neoh KG, Huang W (2001) Modification of gold surface by grafting of poly(ethylene glycol) for reduction in protein adsorption and platelet adhesion. J Biomater Sci Polym Ed 12:515–531

    Article  PubMed  CAS  Google Scholar 

  154. Kah JC, Wong KY, Neoh KG, Song JH, Fu JW, Mhaisalkar S, Olivo M, Sheppard CJ (2009) Critical parameters in the pegylation of gold nanoshells for biomedical applications: an in vitro macrophage study. J Drug Target 17:181–193

    Article  PubMed  CAS  Google Scholar 

  155. Niidome T, Yamagata M, Okamoto Y, Akiyama Y, Takahashi H, Kawano T, Katayama Y, Niidome Y (2006) PEG-modified gold nanorods with a stealth character for in vivo applications. J Control Release 114:343–347

    Article  PubMed  CAS  Google Scholar 

  156. Boisselier E, Salmon L, Ruiz J, Astruc D (2008) How to very efficiently functionalize gold nanoparticles by “click” chemistry. Chem Commun (Camb): 5788–5790

    Google Scholar 

  157. Maus L, Spatz JP, Fiammengo R (2009) Quantification and reactivity of functional groups in the ligand shell of PEGylated gold nanoparticles via a fluorescence-based assay. Langmuir 25:7910–7917

    Article  PubMed  CAS  Google Scholar 

  158. Liu Y, Shipton MK, Ryan J, Kaufman ED, Franzen S, Feldheim DL (2007) Synthesis, stability, and cellular internalization of gold nanoparticles containing mixed peptide-poly(ethylene glycol) monolayers. Anal Chem 79:2221–2229

    Article  PubMed  CAS  Google Scholar 

  159. Miyamoto D, Oishi M, Kojima K, Yoshimoto K, Nagasaki Y (2008) Completely dispersible PEGylated gold nanoparticles under physiological conditions: modification of gold nanoparticles with precisely controlled PEG-b-polyamine. Langmuir 24:5010–5017

    Article  PubMed  CAS  Google Scholar 

  160. Mejias N, Serra-Muns A, Pleixats R, Shafir A, Tristany M (2009) Water-soluble metal nanoparticles with PEG-tagged 15-membered azamacrocycles as stabilizers. Dalton Trans: 7748–7755

    Google Scholar 

  161. von Maltzahn G, Park JH, Agrawal A, Bandaru NK, Das SK, Sailor MJ, Bhatia SN (2009) Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas. Cancer Res 69:3892–3900

    Article  CAS  Google Scholar 

  162. Gu YJ, Cheng J, Lin CC, Lam YW, Cheng SH, Wong WT (2009) Nuclear penetration of surface functionalized gold nanoparticles. Toxicol Appl Pharmacol 237:196–204

    Article  PubMed  CAS  Google Scholar 

  163. Kim D, Park S, Lee JH, Jeong YY, Jon S (2007) Antibiofouling polymer-coated gold nanoparticles as a contrast agent for in vivo X-ray computed tomography imaging. J Am Chem Soc 129:7661–7665

    Article  PubMed  CAS  Google Scholar 

  164. Shenoy D, Fu W, Li J, Crasto C, Jones G, DiMarzio C, Sridhar S, Amiji M (2006) Surface functionalization of gold nanoparticles using hetero-bifunctional poly(ethylene glycol) spacer for intracellular tracking and delivery. Int J Nanomedicine 1:51–57

    Article  PubMed  CAS  Google Scholar 

  165. Lee H, Larson RG (2009) Molecular dynamics study of the structure and interparticle interactions of polyethylene glycol-conjugated PAMAM dendrimers. J Phys Chem B 113:13202–13207

    Article  PubMed  CAS  Google Scholar 

  166. Kaminskas LM, Kelly BD, McLeod VM, Boyd BJ, Krippner GY, Williams ED, Porter CJ (2009) Pharmacokinetics and tumor disposition of PEGylated, methotrexate conjugated poly-l-lysine dendrimers. Mol Pharm 6:1190–1204

    Article  PubMed  CAS  Google Scholar 

  167. Kaminskas LM, Boyd BJ, Karellas P, Krippner GY, Lessene R, Kelly B, Porter CJ (2008) The impact of molecular weight and PEG chain length on the systemic pharmacokinetics of PEGylated poly l-lysine dendrimers. Mol Pharm 5:449–463

    Article  PubMed  CAS  Google Scholar 

  168. Kaminskas LM, Wu Z, Barlow N, Krippner GY, Boyd BJ, Porter CJ (2009) Partly-PEGylated Poly-l-lysine dendrimers have reduced plasma stability and circulation times compared with fully PEGylated dendrimers. J Pharm Sci 98:3871–3875

    Article  PubMed  CAS  Google Scholar 

  169. Kim Y, Klutz AM, Jacobson KA (2008) Systematic investigation of polyamidoamine dendrimers surface-modified with poly(ethylene glycol) for drug delivery applications: synthesis, characterization, and evaluation of cytotoxicity. Bioconjug Chem 19:1660–1672

    Article  PubMed  CAS  Google Scholar 

  170. Kojima C, Regino C, Umeda Y, Kobayashi H, Kono K (2010) Influence of dendrimer generation and polyethylene glycol length on the biodistribution of PEGylated dendrimers. Int J Pharm 383:293–296

    Article  PubMed  CAS  Google Scholar 

  171. Lim J, Guo Y, Rostollan CL, Stanfield J, Hsieh JT, Sun X, Simanek EE (2008) The role of the size and number of polyethylene glycol chains in the biodistribution and tumor localization of triazine dendrimers. Mol Pharm 5:540–547

    Article  PubMed  CAS  Google Scholar 

  172. Yang H, Lopina ST, DiPersio LP, Schmidt SP (2008) Stealth dendrimers for drug delivery: correlation between PEGylation, cytocompatibility, and drug payload. J Mater Sci Mater Med 19:1991–1997

    Article  PubMed  CAS  Google Scholar 

  173. Kaminskas LM, Kota J, McLeod VM, Kelly BD, Karellas P, Porter CJ (2009) PEGylation of polylysine dendrimers improves absorption and lymphatic targeting following SC administration in rats. J Control Release 140:108–116

    Article  PubMed  CAS  Google Scholar 

  174. Lopez AI, Reins RY, McDermott AM, Trautner BW, Cai C (2009) Antibacterial activity and cytotoxicity of PEGylated poly(amidoamine) dendrimers. Mol Biosyst 5:1148–1156

    Article  PubMed  CAS  Google Scholar 

  175. Wang W, Xiong W, Wan J, Sun X, Xu H, Yang X (2009) The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress. Nanotechnology 20:105103

    Article  PubMed  CAS  Google Scholar 

  176. Kono K, Kojima C, Hayashi N, Nishisaka E, Kiura K, Watarai S, Harada A (2008) Preparation and cytotoxic activity of poly(ethylene glycol)-modified poly(amidoamine) dendrimers bearing adriamycin. Biomaterials 29:1664–1675

    Article  PubMed  CAS  Google Scholar 

  177. Yang H, Lopina ST (2007) Stealth dendrimers for antiarrhythmic quinidine delivery. J Mater Sci Mater Med 18:2061–2065

    Article  PubMed  CAS  Google Scholar 

  178. Kojima C, Toi Y, Harada A, Kono K (2007) Preparation of poly(ethylene glycol)-attached dendrimers encapsulating photosensitizers for application to photodynamic therapy. Bioconjug Chem 18:663–670

    Article  PubMed  CAS  Google Scholar 

  179. Bhadra D, Bhadra S, Jain NK (2006) PEGylated peptide dendrimeric carriers for the delivery of antimalarial drug chloroquine phosphate. Pharm Res 23:623–633

    Article  PubMed  CAS  Google Scholar 

  180. Gajbhiye V, Vijayaraj Kumar P, Tekade RK, Jain NK (2009) PEGylated PPI dendritic architectures for sustained delivery of H2 receptor antagonist. Eur J Med Chem 44:1155–1166

    Article  PubMed  CAS  Google Scholar 

  181. Taratula O, Garbuzenko OB, Kirkpatrick P, Pandya I, Savla R, Pozharov VP, He H, Minko T (2009) Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery. J Control Release 140:284–293

    Article  PubMed  CAS  Google Scholar 

  182. Ke W, Shao K, Huang R, Han L, Liu Y, Li J, Kuang Y, Ye L, Lou J, Jiang C (2009) Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer. Biomaterials 30:6976–6985

    Article  PubMed  CAS  Google Scholar 

  183. Qi R, Gao Y, Tang Y, He RR, Liu TL, He Y, Sun S, Li BY, Li YB, Liu G (2009) PEG-conjugated PAMAM dendrimers mediate efficient intramuscular gene expression. AAPS J 11:395–405

    Article  PubMed  CAS  Google Scholar 

  184. Sweet DM, Kolhatkar RB, Ray A, Swaan P, Ghandehari H (2009) Transepithelial transport of PEGylated anionic poly(amidoamine) dendrimers: implications for oral drug delivery. J Control Release 138:78–85

    Article  PubMed  CAS  Google Scholar 

  185. Bai S, Ahsan F (2009) Synthesis and evaluation of pegylated dendrimeric nanocarrier for pulmonary delivery of low molecular weight heparin. Pharm Res 26:539–548

    Article  PubMed  CAS  Google Scholar 

  186. Haba Y, Kojima C, Harada A, Ura T, Horinaka H, Kono K (2007) Preparation of poly(ethylene glycol)-modified poly(amido amine) dendrimers encapsulating gold nanoparticles and their heat-generating ability. Langmuir 23:5243–5246

    Article  PubMed  CAS  Google Scholar 

  187. Liu Z, Tabakman SM, Chen Z, Dai H (2009) Preparation of carbon nanotube bioconjugates for biomedical applications. Nat Protoc 4:1372–1382

    Article  PubMed  CAS  Google Scholar 

  188. Murray AR, Kisin E, Leonard SS, Young SH, Kommineni C, Kagan VE, Castranova V, Shvedova AA (2009) Oxidative stress and inflammatory response in dermal toxicity of single-walled carbon nanotubes. Toxicology 257:161–171

    Article  PubMed  CAS  Google Scholar 

  189. Cheng J, Fernando KA, Veca LM, Sun YP, Lamond AI, Lam YW, Cheng SH (2008) Reversible accumulation of PEGylated single-walled carbon nanotubes in the mammalian nucleus. ACS Nano 2:2085–2094

    Article  PubMed  CAS  Google Scholar 

  190. Murakami T, Sawada H, Tamura G, Yudasaka M, Iijima S, Tsuchida K (2008) Water-dispersed single-wall carbon nanohorns as drug carriers for local cancer chemotherapy. Nanomedicine (Lond) 3:453–463

    Article  CAS  Google Scholar 

  191. Delogu LG, Magrini A, Bergamaschi A, Rosato N, Dawson MI, Bottini N, Bottini M (2009) Conjugation of antisense oligonucleotides to PEGylated carbon nanotubes enables efficient knockdown of PTPN22 in T lymphocytes. Bioconjug Chem 20:427–431

    Article  PubMed  CAS  Google Scholar 

  192. Schipper ML, Iyer G, Koh AL, Cheng Z, Ebenstein Y, Aharoni A, Keren S, Bentolila LA, Li J, Rao J, Chen X, Banin U, Wu AM, Sinclair R, Weiss S, Gambhir SS (2009) Particle size, surface coating, and PEGylation influence the biodistribution of quantum dots in living mice. Small 5:126–134

    Article  PubMed  CAS  Google Scholar 

  193. Susumu K, Mei BC, Mattoussi H (2009) Multifunctional ligands based on dihydrolipoic acid and polyethylene glycol to promote biocompatibility of quantum dots. Nat Protoc 4:424–436

    Article  PubMed  CAS  Google Scholar 

  194. Warnement MR, Tomlinson ID, Chang JC, Schreuder MA, Luckabaugh CM, Rosenthal SJ (2008) Controlling the reactivity of ampiphilic quantum dots in biological assays through hydrophobic assembly of custom PEG derivatives. Bioconjug Chem 19:1404–1413

    Article  PubMed  CAS  Google Scholar 

  195. Daou TJ, Li L, Reiss P, Josserand V, Texier I (2009) Effect of poly(ethylene glycol) length on the in vivo behavior of coated quantum dots. Langmuir 25:3040–3044

    Article  PubMed  CAS  Google Scholar 

  196. Tomlinson ID, Gies AP, Gresch PJ, Dillard J, Orndorff RL, Sanders-Bush E, Hercules DM, Rosenthal SJ (2006) Universal polyethylene glycol linkers for attaching receptor ligands to quantum dots. Bioorg Med Chem Lett 16:6262–6266

    Article  PubMed  CAS  Google Scholar 

  197. Lee J, Kim J, Park E, Jo S, Song R (2008) PEG-ylated cationic CdSe/ZnS QDs as an efficient intracellular labeling agent. Phys Chem Chem Phys 10:1739–1742

    Article  PubMed  CAS  Google Scholar 

  198. Wan F, You J, Sun Y, Zhang XG, Cui FD, Du YZ, Yuan H, Hu FQ (2008) Studies on PEG-modified SLNs loading vinorelbine bitartrate (I): preparation and evaluation in vitro. Int J Pharm 359:104–110

    Article  PubMed  CAS  Google Scholar 

  199. Jayagopal A, Sussman EM, Shastri VP (2008) Functionalized solid lipid nanoparticles for transendothelial delivery. IEEE Trans Nanobiosci 7:28–34

    Article  CAS  Google Scholar 

  200. Maitani Y, Hattori Y (2009) Oligoarginine-PEG-lipid particles for gene delivery. Expert Opin Drug Deliv 6:1065–1077

    Article  PubMed  CAS  Google Scholar 

  201. Murad KL, Mahany KL, Brugnara C, Kuypers FA, Eaton JW, Scott MD (1999) Structural and functional consequences of antigenic modulation of red blood cells with methoxypoly(ethylene glycol). Blood 93:2121–2127

    PubMed  CAS  Google Scholar 

  202. Scott MD, Chen AM (2004) Beyond the red cell: pegylation of other blood cells and tissues. Transfus Clin Biol 11:40–46

    Article  PubMed  Google Scholar 

  203. Scott MD, Murad KL (1998) Cellular camouflage: fooling the immune system with polymers. Curr Pharm Des 4:423–438

    PubMed  CAS  Google Scholar 

  204. Abra RM, Bankert RB, Chen F, Egilmez NK, Huang K, Saville R, Slater JL, Sugano M, Yokota SJ (2002) The next generation of liposome delivery systems: recent experience with tumor-targeted, sterically-stabilized immunoliposomes and active-loading gradients. J Liposome Res 12:1–3

    Article  PubMed  CAS  Google Scholar 

  205. Blume G, Cevc G, Crommelin MD, Bakker-Woudenberg IA, Kluft C, Storm G (1993) Specific targeting with poly(ethylene glycol)-modified liposomes: coupling of homing devices to the ends of the polymeric chains combines effective target binding with long circulation times. Biochim Biophys Acta 1149:180–184

    Article  PubMed  CAS  Google Scholar 

  206. Torchilin VP, Klibanov AL, Huang L, O’Donnell S, Nossiff ND, Khaw BA (1992) Targeted accumulation of polyethylene glycol-coated immunoliposomes in infarcted rabbit myocardium. FASEB J 6:2716–2719

    PubMed  CAS  Google Scholar 

  207. Torchilin VP, Levchenko TS, Lukyanov AN, Khaw BA, Klibanov AL, Rammohan R, Samokhin GP, Whiteman KR (2001) p-Nitrophenylcarbonyl-PEG-PE-liposomes: fast and simple attachment of specific ligands, including monoclonal antibodies, to distal ends of PEG chains via p-nitrophenylcarbonyl groups. Biochim Biophys Acta 1511:397–411

    Article  PubMed  CAS  Google Scholar 

  208. Zalipsky S, Gittelman J, Mullah N, Qazen MM, Harding JA (1998) Biologically active ligand-bearing polymer-grafted liposomes. In: Gregoriadis G (ed) Targeting of drugs 6: strategies for stealth therapeutic systems. Plenum, New York, pp 131–139

    Google Scholar 

  209. Torchilin VP, Lukyanov AN, Gao Z, Papahadjopoulos-Sternberg B (2003) Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs. Proc Natl Acad Sci USA 100:6039–6044

    Article  PubMed  CAS  Google Scholar 

  210. Torchilin VP, Rammohan R, Weissig V, Khaw BA, Klibanov A, Samokhin GP (2000) PEG-Immunoliposomes: attachment of monoclonal antibody to distal ends of PEG chains via p-Nitrophenylcarbonyl groups. In: 27th international symposium on controlled release of bioactive materials, Controlled Release Society, Inc., Paris, pp 217–218

    Google Scholar 

  211. Zalipsky S, Mullah N, Harding JA, Gittelman J, Guo L, DeFrees SA (1997) Poly(ethylene glycol)-grafted liposomes with oligopeptide or oligosaccharide ligands appended to the termini of the polymer chains. Bioconjug Chem 8:111–118

    Article  PubMed  CAS  Google Scholar 

  212. DeFrees SA, Phillips L, Guo L, Zalipsky S (1996) Sialyl Lewis x liposomes as a multivalent ligand and inhibitor of E-selectin mediated cellular adhesion. J Am Chem Soc 118:6101–6104

    Article  CAS  Google Scholar 

  213. Gabizon A, Horowitz AT, Goren D, Tzemach D, Mandelbaum-Shavit F, Qazen MM, Zalipsky S (1999) Targeting folate receptor with folate linked to extremities of poly(ethylene glycol)-grafted liposomes: in vitro studies. Bioconjug Chem 10:289–298

    Article  PubMed  CAS  Google Scholar 

  214. Wong JY, Kuhl TL, Israelachvili JN, Mullah N, Zalipsky S (1997) Direct measurement of a tethered ligand-receptor interaction potential. Science 275:820–822

    Article  PubMed  CAS  Google Scholar 

  215. Gao J, Zhong W, He J, Li H, Zhang H, Zhou G, Li B, Lu Y, Zou H, Kou G, Zhang D, Wang H, Guo Y, Zhong Y (2009) Tumor-targeted PE38KDEL delivery via PEGylated anti-HER2 immunoliposomes. Int J Pharm 374:145–152

    Article  PubMed  CAS  Google Scholar 

  216. Park JW, Kirpotin DB, Hong K, Shalaby R, Shao Y, Nielsen UB, Marks JD, Papahadjopoulos D, Benz CC (2001) Tumor targeting using anti-her2 immunoliposomes. J Control Release 74:95–113

    Article  PubMed  CAS  Google Scholar 

  217. Kamps JA, Koning GA, Velinova MJ, Morselt HW, Wilkens M, Gorter A, Donga J, Scherphof GL (2000) Uptake of long-circulating immunoliposomes, directed against colon adenocarcinoma cells, by liver metastases of colon cancer. J Drug Target 8:235–245

    Article  PubMed  CAS  Google Scholar 

  218. ElBayoumi TA, Torchilin VP (2009) Tumor-targeted nanomedicines: enhanced antitumor efficacy in vivo of doxorubicin-loaded, long-circulating liposomes modified with cancer-specific monoclonal antibody. Clin Cancer Res 15:1973–1980

    Article  PubMed  CAS  Google Scholar 

  219. Lukyanov AN, Elbayoumi TA, Chakilam AR, Torchilin VP (2004) Tumor-targeted liposomes: doxorubicin-loaded long-circulating liposomes modified with anti-cancer antibody. J Control Release 100:135–144

    Article  PubMed  CAS  Google Scholar 

  220. Brannon-Peppas L, Blanchette JO (2004) Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 56:1649–1659

    Article  PubMed  CAS  Google Scholar 

  221. Olivier JC, Huertas R, Lee HJ, Calon F, Pardridge WM (2002) Synthesis of pegylated immunonanoparticles. Pharm Res 19:1137–1143

    Article  PubMed  CAS  Google Scholar 

  222. Eck W, Craig G, Sigdel A, Ritter G, Old LJ, Tang L, Brennan MF, Allen PJ, Mason MD (2008) PEGylated gold nanoparticles conjugated to monoclonal F19 antibodies as targeted labeling agents for human pancreatic carcinoma tissue. ACS Nano 2:2263–2272

    Article  PubMed  CAS  Google Scholar 

  223. Cato MH, D’Annibale F, Mills DM, Cerignoli F, Dawson MI, Bergamaschi E, Bottini N, Magrini A, Bergamaschi A, Rosato N, Rickert RC, Mustelin T, Bottini M (2008) Cell-type specific and cytoplasmic targeting of PEGylated carbon nanotube-based nanoassemblies. J Nanosci Nanotechnol 8:2259–2269

    Article  PubMed  CAS  Google Scholar 

  224. Kato K, Itoh C, Yasukouchi T, Nagamune T (2004) Rapid protein anchoring into the membranes of mammalian cells using oleyl chain and poly(ethylene glycol) derivatives. Biotechnol Prog 20:897–904

    Article  PubMed  CAS  Google Scholar 

  225. Hatakeyama H, Akita H, Maruyama K, Suhara T, Harashima H (2004) Factors governing the in vivo tissue uptake of transferrin-coupled polyethylene glycol liposomes in vivo. Int J Pharm 281:25–33

    Article  PubMed  CAS  Google Scholar 

  226. Ishida O, Maruyama K, Tanahashi H, Iwatsuru M, Sasaki K, Eriguchi M, Yanagie H (2001) Liposomes bearing polyethyleneglycol-coupled transferrin with intracellular targeting property to the solid tumors in vivo. Pharm Res 18:1042–1048

    Article  PubMed  CAS  Google Scholar 

  227. Derycke AS, De Witte PA (2002) Transferrin-mediated targeting of hypericin embedded in sterically stabilized PEG-liposomes. Int J Oncol 20:181–187

    PubMed  CAS  Google Scholar 

  228. Gijsens A, Derycke A, Missiaen L, De Vos D, Huwyler J, Eberle A, de Witte P (2002) Targeting of the photocytotoxic compound AlPcS4 to Hela cells by transferrin conjugated PEG-liposomes. Int J Cancer 101:78–85

    Article  PubMed  CAS  Google Scholar 

  229. Iinuma H, Maruyama K, Okinaga K, Sasaki K, Sekine T, Ishida O, Ogiwara N, Johkura K, Yonemura Y (2002) Intracellular targeting therapy of cisplatin-encapsulated transferrin-polyethylene glycol liposome on peritoneal dissemination of gastric cancer. Int J Cancer 99:130–137

    Article  PubMed  CAS  Google Scholar 

  230. Li X, Ding L, Xu Y, Wang Y, Ping Q (2009) Targeted delivery of doxorubicin using stealth liposomes modified with transferrin. Int J Pharm 373:116–123

    Article  PubMed  CAS  Google Scholar 

  231. Doi A, Kawabata S, Iida K, Yokoyama K, Kajimoto Y, Kuroiwa T, Shirakawa T, Kirihata M, Kasaoka S, Maruyama K, Kumada H, Sakurai Y, Masunaga S, Ono K, Miyatake S (2008) Tumor-specific targeting of sodium borocaptate (BSH) to malignant glioma by transferrin-PEG liposomes: a modality for boron neutron capture therapy. J Neurooncol 87:287–294

    Article  PubMed  CAS  Google Scholar 

  232. Omori N, Maruyama K, Jin G, Li F, Wang SJ, Hamakawa Y, Sato K, Nagano I, Shoji M, Abe K (2003) Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin. Neurol Res 25:275–279

    Article  PubMed  CAS  Google Scholar 

  233. Li Y, Ogris M, Wagner E, Pelisek J, Ruffer M (2003) Nanoparticles bearing polyethyleneglycol-coupled transferrin as gene carriers: preparation and in vitro evaluation. Int J Pharm 259:93–101

    Article  PubMed  CAS  Google Scholar 

  234. Leamon CP, Low PS (1991) Delivery of macromolecules into living cells: a method that exploits folate receptor endocytosis. Proc Natl Acad Sci USA 88:5572–5576

    Article  PubMed  CAS  Google Scholar 

  235. Lee RJ, Low PS (1994) Delivery of liposomes into cultured KB cells via folate receptor-mediated endocytosis. J Biol Chem 269:3198–3204

    PubMed  CAS  Google Scholar 

  236. Gabizon A, Shmeeda H, Horowitz AT, Zalipsky S (2004) Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid-PEG conjugates. Adv Drug Deliv Rev 56:1177–1192

    Article  PubMed  CAS  Google Scholar 

  237. Lu Y, Low PS (2002) Folate-mediated delivery of macromolecular anticancer therapeutic agents. Adv Drug Deliv Rev 54:675–693

    Article  PubMed  CAS  Google Scholar 

  238. Stella B, Arpicco S, Peracchia MT, Desmaele D, Hoebeke J, Renoir M, D’Angelo J, Cattel L, Couvreur P (2000) Design of folic acid-conjugated nanoparticles for drug targeting. J Pharm Sci 89:1452–1464

    Article  PubMed  CAS  Google Scholar 

  239. Park EK, Lee SB, Lee YM (2005) Preparation and characterization of methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folate-mediated targeting of anticancer drugs. Biomaterials 26:1053–1061

    Article  PubMed  CAS  Google Scholar 

  240. Choi H, Choi SR, Zhou R, Kung HF, Chen IW (2004) Iron oxide nanoparticles as magnetic resonance contrast agent for tumor imaging via folate receptor-targeted delivery. Acad Radiol 11:996–1004

    Article  PubMed  Google Scholar 

  241. Zhang Y, Kohler N, Zhang M (2002) Surface modification of superparamagnetic magnetite nanoparticles and their intracellular uptake. Biomaterials 23:1553–1561

    Article  PubMed  CAS  Google Scholar 

  242. Wu L, Tang C, Yin C (2009) Folate-mediated solid-liquid lipid nanoparticles for paclitaxel coated poly(ethylene glycol). Drug Dev Ind Pharm 36(4):439–448

    Article  Google Scholar 

  243. Liang B, He ML, Xiao ZP, Li Y, Chan CY, Kung HF, Shuai XT, Peng Y (2008) Synthesis and characterization of folate-PEG-grafted-hyperbranched-PEI for tumor-targeted gene delivery. Biochem Biophys Res Commun 367:874–880

    Article  PubMed  CAS  Google Scholar 

  244. Esmaeili F, Ghahremani MH, Ostad SN, Atyabi F, Seyedabadi M, Malekshahi 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

    Article  PubMed  CAS  Google Scholar 

  245. Singh P, Gupta U, Asthana A, Jain NK (2008) Folate and folate-PEG-PAMAM dendrimers: synthesis, characterization, and targeted anticancer drug delivery potential in tumor bearing mice. Bioconjug Chem 19:2239–2252

    Article  PubMed  CAS  Google Scholar 

  246. Dixit V, Van den Bossche J, Sherman DM, Thompson DH, Andres RP (2006) Synthesis and grafting of thioctic acid-PEG-folate conjugates onto Au nanoparticles for selective targeting of folate receptor-positive tumor cells. Bioconjug Chem 17:603–609

    Article  PubMed  CAS  Google Scholar 

  247. Song EQ, Zhang ZL, Luo QY, Lu W, Shi YB, Pang DW (2009) Tumor cell targeting using folate-conjugated fluorescent quantum dots and receptor-mediated endocytosis. Clin Chem 55:955–963

    Article  PubMed  CAS  Google Scholar 

  248. Dhar S, Liu Z, Thomale J, Dai H, Lippard SJ (2008) Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device. J Am Chem Soc 130:11467–11476

    Article  PubMed  CAS  Google Scholar 

  249. Ou Z, Wu B, Xing D, Zhou F, Wang H, Tang Y (2009) Functional single-walled carbon nanotubes based on an integrin alpha v beta 3 monoclonal antibody for highly efficient cancer cell targeting. Nanotechnology 20:105102

    Article  PubMed  CAS  Google Scholar 

  250. Dagar S, Krishnadas A, Rubinstein I, Blend MJ, Onyuksel H (2003) VIP grafted sterically stabilized liposomes for targeted imaging of breast cancer: in vivo studies. J Control Release 91:123–133

    Article  PubMed  CAS  Google Scholar 

  251. Schiffelers RM, Koning GA, ten Hagen TL, Fens MH, Schraa AJ, Janssen AP, Kok RJ, Molema G, Storm G (2003) Anti-tumor efficacy of tumor vasculature-targeted liposomal doxorubicin. J Control Release 91:115–122

    Article  PubMed  CAS  Google Scholar 

  252. Garg A, Tisdale AW, Haidari E, Kokkoli E (2009) Targeting colon cancer cells using PEGylated liposomes modified with a fibronectin-mimetic peptide. Int J Pharm 366:201–210

    Article  PubMed  CAS  Google Scholar 

  253. Demirgoz D, Garg A, Kokkoli E (2008) PR_b-targeted PEGylated liposomes for prostate cancer therapy. Langmuir 24:13518–13524

    Article  PubMed  CAS  Google Scholar 

  254. Yokoe J, Sakuragi S, Yamamoto K, Teragaki T, Ogawara K, Higaki K, Katayama N, Kai T, Sato M, Kimura T (2008) Albumin-conjugated PEG liposome enhances tumor distribution of liposomal doxorubicin in rats. Int J Pharm 353:28–34

    Article  PubMed  CAS  Google Scholar 

  255. Hu K, Li J, Shen Y, Lu W, Gao X, Zhang Q, Jiang X (2009) Lactoferrin-conjugated PEG-PLA nanoparticles with improved brain delivery: in vitro and in vivo evaluations. J Control Release 134:55–61

    Article  PubMed  CAS  Google Scholar 

  256. Sawant RR, Sawant RM, Kale AA, Torchilin VP (2008) The architecture of ligand attachment to nanocarriers controls their specific interaction with target cells. J Drug Target 16:596–600

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, 02129, USA

    Vladimir Torchilin

Authors
  1. Vladimir Torchilin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vladimir Torchilin .

Editor information

Editors and Affiliations

  1. Cuesta Drive 631, Los Altos, 94024, USA

    Jeremy C. Wright

  2. Browns Road 626, Storrs, 06268, Connecticut, USA

    Diane J. Burgess

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Controlled Release Society

About this chapter

Cite this chapter

Torchilin, V. (2012). PEGylated Pharmaceutical Nanocarriers. In: Wright, J., Burgess, D. (eds) Long Acting Injections and Implants. Advances in Delivery Science and Technology. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0554-2_14

Download citation

Publish with us

Policies and ethics

Societies and partnerships

Search

Navigation