Skip to main content

Nanomedicine

Clinical Applications of Polyethylene Glycol Conjugated Proteins and Drugs

Clinical Pharmacokinetics volume 45, pages 965–988 (2006)Cite this article

Abstract

The intricate problems associated with the delivery and various unnecessary in vivo transitions of proteins and drugs needs to be tackled soon to be able to exploit the myriad of putative therapeutics created by the biotechnology boom. Nanomedicine is one of the most promising applications of nanotechnology in the field of medicine. It has been defined as the monitoring, repair, construction and control of human biological systems at the molecular level using engineered nanodevices and nanostructures. These nanostructured medicines will eventually turn the world of drug delivery upside down.

PEGylation (i.e. the attachment of polyethylene glycol to proteins and drugs) is an upcoming methodology for drug development and it has the potential to revolutionise medicine by drastically improving the pharmacokinetic and pharmacodynamic properties of the administered drug. This article provides a total strategy for improving the therapeutic efficacy of various biotechnological products in drug delivery. This article also presents an extensive analysis of most of the PEGylated proteins, peptides and drugs, together with extensive clinical data. Nanomedicines and PEGylation, the latest offshoots of nanotechnology will definitely pave a way in the field of drug delivery where targeted delivery, formulation, in vivo stability and retention are the major challenges.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Table I
Table II
Fig. 2
Table III
Fig. 3
Table IV
Table V
Table VI
Fig. 4
Table VII

Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Winau F, Westphal O, Winau R. Paul Ehrlich: in search of the magic bullet. Microbes Infect 2004; 6: 786–9

    PubMed  CAS  Article  Google Scholar 

  2. Sahoo SK. Applications of nanomedicine. Asia Pacific Biotech News 2005; 9: 1048–50

    Article  Google Scholar 

  3. Duncan R. The dawning era of polymer therapeutics. Nat Rev Drug Discov 2003; 2: 347–60

    PubMed  CAS  Article  Google Scholar 

  4. Allen TM. Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2002; 2: 750–63

    PubMed  CAS  Article  Google Scholar 

  5. Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005; 4: 145–60

    PubMed  CAS  Article  Google Scholar 

  6. Shaffer C. Nanomedicine transforms drug delivery. Drug Discov Today 2005; 10: 1581–2

    PubMed  Article  Google Scholar 

  7. Freitas Jr RA. What is nanomedicine? Dis Mon 2005; 51: 325–41

    PubMed  Article  Google Scholar 

  8. Moghimi SM, Hunter AC, Murray JC. Nanomedicine: current status and future prospects. FASEB J 2005; 19: 311–30

    PubMed  CAS  Article  Google Scholar 

  9. Thanou M, Duncan R. Polymer-protein and polymer-drug conjugates in cancer therapy. Curr Opin Investig Drugs 2003; 4: 701–9

    PubMed  CAS  Google Scholar 

  10. Kayser O, Lemke A, Hernandez-Trejo N. The impact of nanobiotechnology on the development of new drug delivery systems. Curr Pharm Biotechnol 2005; 6: 3–5

    PubMed  CAS  Google Scholar 

  11. Mainardes RM, Silva LP. Drug delivery systems: past, present, and future. Curr Drug Targets 2004; 5: 449–55

    PubMed  CAS  Article  Google Scholar 

  12. Hamman JH, Enslin GM, Kotze AF. Oral delivery of peptide drugs: barriers and developments. BioDrugs 2005; 19: 165–77

    PubMed  CAS  Article  Google Scholar 

  13. Pawar R, Ben-Ari A, Domb AJ. Protein and peptide parenteral controlled delivery. Expert Opin Biol Ther 2004; 4: 1203–12

    PubMed  CAS  Article  Google Scholar 

  14. Orive G, Hernandez RM, Rodriguez Gascon A, et al. Drug delivery in biotechnology: present and future. Curr Opin Biotechnol 2003; 14: 659–64

    PubMed  CAS  Article  Google Scholar 

  15. Brown LR. Commercial challenges of protein drug delivery. Expert Opin Drug Deliv 2005; 2: 29–42

    PubMed  Article  Google Scholar 

  16. Sato H, Sugiyama Y, Tsuji A, et al. Importance of receptor-mediated endocytosis in peptide delivery and targeting: kinetic aspects. Adv Drug Deliv Rev 1996; 19: 445–67

    CAS  Article  Google Scholar 

  17. Hashida M, Nishikawa M, Yamashita F, et al. Cell-specific delivery of genes with glycosylated carriers. Adv Drug Deliv Rev 2001; 52: 187–96

    PubMed  CAS  Article  Google Scholar 

  18. Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000; 11: 265–83

    PubMed  CAS  Article  Google Scholar 

  19. Links M, Brown R. Clinical relevance of the molecular mechanisms of resistance to anti-cancer drugs. Expert Rev Mol Med 1999; 1999: 1–21

    PubMed  CAS  Google Scholar 

  20. Abuchowski A, McCoy JR, Palczuk NC, et al. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase. J Biol Chem 1977; 252: 3582–6

    PubMed  CAS  Google Scholar 

  21. Conti S, Polonelli L, Frazzi R, et al. Controlled delivery of biotechnological products. Curr Pharm Biotechnol 2000; 1: 313–23

    PubMed  CAS  Article  Google Scholar 

  22. Qiu LY, Bae YH. Polymer architecture and drug delivery. Pharm Res 2006; 23: 1–30

    PubMed  CAS  Article  Google Scholar 

  23. Kumar MN, Kumar N. Polymeric controlled drug-delivery systems: perspective issues and opportunities. Drug Dev Ind Pharm 2001; 27: 1–30

    PubMed  CAS  Article  Google Scholar 

  24. Kanjickal DG, Lopina ST. Modeling of drug release from polymeric delivery systems: a review. Crit Rev Ther Drug Carrier Syst 2004; 21: 345–86

    PubMed  CAS  Article  Google Scholar 

  25. Torchilin VP, Trubetskoy VS. Which polymers can make nanoparticulate drug carriers long-circulating? Adv Drug Deliv Rev 1995; 16: 141–55

    CAS  Article  Google Scholar 

  26. Torchilin VP. Polymer-coated long-circulating microparticulate pharmaceuticals. J Microencapsul 1998; 15: 1–19

    PubMed  CAS  Article  Google Scholar 

  27. Hoste K, De Winne K, Schacht E. Polymeric prodrugs. Int J Pharm 2004; 277: 119–31

    PubMed  CAS  Article  Google Scholar 

  28. Gref R, Minamitake Y, Peracchia MT, et al. Biodegradable long-circulating polymeric nanospheres. Science 1994; 263: 1600–3

    PubMed  CAS  Article  Google Scholar 

  29. Harris JM, Martin NE, Modi M. Pegylation: a novel process for modifying pharmacokinetics. Clin Pharmacokinet 2001; 40: 539–51

    PubMed  CAS  Article  Google Scholar 

  30. Delgado C, Francis GE, Fisher D. The uses and properties of PEG-linked proteins. Crit Rev Ther Drug Carrier Syst 1992; 9: 249–304

    PubMed  CAS  Google Scholar 

  31. Abuchowski A, van Es T, Palczuk NC, et al. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J Biol Chem 1977; 252: 3578–81

    PubMed  CAS  Google Scholar 

  32. Molineux G. Pegylation: engineering improved pharmaceuticals for enhanced therapy. Cancer Treat Rev 2002; 28 Suppl. A: 13–6

    PubMed  CAS  Article  Google Scholar 

  33. Yowell SL, Blackwell S. Novel effects with polyethylene glycol modified pharmaceuticals. Cancer Treat Rev 2002; 28 Suppl. A: 3–6

    PubMed  CAS  Article  Google Scholar 

  34. Maeda H. SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv Drug Deliv Rev 2001; 46: 169–85

    PubMed  CAS  Article  Google Scholar 

  35. Vasey PA, Kaye SB, Morrison R, et al. Phase I clinical and pharmacokinetic study of PK1 [N-(2-hydroxypropyl) methacrylamide copolymer doxorubicin]: first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Cancer Research Campaign Phase I/II Committee. Clin Cancer Res 1999; 5: 83–94

    PubMed  CAS  Google Scholar 

  36. Huang PS, Oliff A. Drug-targeting strategies in cancer therapy. Curr Opin Genet Dev 2001; 11: 104–10

    PubMed  CAS  Article  Google Scholar 

  37. Seymour LW, Ferry DR, Anderson D, et al. Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin. J Clin Oncol 2002; 20: 1668–76

    PubMed  CAS  Article  Google Scholar 

  38. Duncan R, Seymour LC, Scarlett L, et al. Fate of N-(2-hydroxypropyl)methacrylamide copolymers with pendent galactosamine residues after intravenous administration to rats. Biochim Biophys Acta 1986; 880: 62–71

    PubMed  CAS  Article  Google Scholar 

  39. Meerum Terwogt JM, ten Bokkel Huinink WW, Schellens JH, et al. Phase I clinical and pharmacokinetic study of PNU166945, a novel water-soluble polymer-conjugated prodrug of paclitaxel. Anticancer Drugs 2001; 12: 315–23

    Article  Google Scholar 

  40. Rice JR, Howell SB. AP-5346 polymer-delivered platinum complex. Drugs Future 2004; 29: 561–5

    CAS  Article  Google Scholar 

  41. Gianasi E, Buckley RG, Latigo J, et al. HPMA copolymers platinates containing dicarboxylato ligands: preparation, characterisation and in vitro and in vivo evaluation. J Drug Target 2002; 10: 549–56

    PubMed  CAS  Article  Google Scholar 

  42. Gianasi E, Wasil M, Evagorou EG, et al. HPMA copolymer platinates as novel antitumour agents: in vitro properties, pharmacokinetics and antitumour activity in vivo. Eur J Cancer 1999; 35: 994–1002

    PubMed  CAS  Article  Google Scholar 

  43. Schoemaker NE, van Kesteren C, Rosing H, et al. A phase I and pharmacokinetic study of MAG-CPT, a water-soluble polymer conjugate of camptothecin. Br J Cancer 2002; 87: 608–14

    PubMed  CAS  Article  Google Scholar 

  44. Garfield D. New form of paclitaxel shows promise. Lancet Oncol 2001; 2: 192

    PubMed  CAS  Article  Google Scholar 

  45. Li C, Yu DF, Newman RA, et al. Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)-paclitaxel conjugate. Cancer Res 1998; 58: 2404–9

    PubMed  CAS  Google Scholar 

  46. Nemunaitis J, Cunningham C, Senzer N, et al. Phase I study of CT-2103, a polymer-conjugated paclitaxel, and carboplatin in patients with advanced solid tumors. Cancer Invest 2005; 23: 671–6

    PubMed  CAS  Article  Google Scholar 

  47. Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2003; 2: 214–21

    PubMed  CAS  Article  Google Scholar 

  48. Mehvar R. Modulation of the pharmacokinetics and pharmacodynamics of proteins by polyethylene glycol conjugation. J Pharm Pharm Sci 2000; 3: 125–36

    PubMed  CAS  Google Scholar 

  49. Veronese FM, Harris JM. Introduction and overview of peptide and protein pegylation. Adv Drug Deliv Rev 2002; 54: 453–6

    PubMed  CAS  Article  Google Scholar 

  50. Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 2002; 54: 459–76

    PubMed  CAS  Article  Google Scholar 

  51. Yamaoka T, Tabata Y, Ikada Y. Distribution and tissue uptake of poly(ethylene glycol) with different molecular weights after intravenous administration to mice. J Pharm Sci 1994; 83: 601–6

    PubMed  CAS  Article  Google Scholar 

  52. Yamaoka T, Tabata Y, Ikada Y. Fate of water-soluble polymers administered via different routes. J Pharm Sci 1995; 84: 349–54

    PubMed  CAS  Article  Google Scholar 

  53. Friman S, Egestad B, Sjovall J, et al. Hepatic excretion and metabolism of polyethylene glycols and mannitol in the cat. J Hepatol 1993; 17: 48–55

    PubMed  CAS  Article  Google Scholar 

  54. Kawai F. Microbial degradation of polyethers. Appl Microbiol Biotechnol 2002; 58: 30–8

    PubMed  CAS  Article  Google Scholar 

  55. Wieder KJ, Palczuk NC, van Es T, et al. Some properties of polyethylene glycol: phenylalanine ammonia-lyase adducts. J Biol Chem 1979; 254: 12579–87

    PubMed  CAS  Google Scholar 

  56. Chapman AP. PEGylated antibodies and antibody fragments for improved therapy: a review. Adv Drug Deliv Rev 2002; 54: 531–45

    PubMed  CAS  Article  Google Scholar 

  57. Boccu E, Velo GP, Veronese FM. Pharmacokinetic properties of polyethylene glycol derivatized superoxide dismutase. Pharmacol Res Commun 1982; 14: 113–20

    PubMed  CAS  Article  Google Scholar 

  58. Beauchamp CO, Gonias SL, Menapace DP, et al. A new procedure for the synthesis of polyethylene glycol-protein adducts; effects on function, receptor recognition, and clearance of superoxide dismutase, lactoferrin, and alpha 2-macroglobulin. Anal Biochem 1983; 131: 25–33

    PubMed  CAS  Article  Google Scholar 

  59. Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 2003; 55: 1261–77

    PubMed  CAS  Article  Google Scholar 

  60. Zalipsky S. Functionalized poly(ethylene glycol) for preparation of biologically relevant conjugates. Bioconjug Chem 1995; 6: 150–65

    PubMed  CAS  Article  Google Scholar 

  61. Francis GE, Fisher D, Delgado C, et al. PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimisation of coupling techniques. Int J Hematol 1998; 68: 1–18

    PubMed  CAS  Article  Google Scholar 

  62. Cunningham-Rundles C, Zhuo Z, Griffith B, et al. Biological activities of polyethylene-glycol immunoglobulin conjugates: resistance to enzymatic degradation. J Immunol Methods 1992; 152: 177–90

    PubMed  CAS  Article  Google Scholar 

  63. Maeda H, Wu J, Sawa T, et al. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 2000; 65: 271–84

    PubMed  CAS  Article  Google Scholar 

  64. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986; 46: 6387–92

    PubMed  CAS  Google Scholar 

  65. Hershfield MS, Buckley RH, Greenberg ML, et al. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med 1987; 316: 589–96

    PubMed  CAS  Article  Google Scholar 

  66. Ho DH, Brown NS, Yen A, et al. Clinical pharmacology of polyethylene glycol-L-asparaginase. Drug Metab Dispos 1986; 14: 349–52

    PubMed  CAS  Google Scholar 

  67. Muss HB, Spell N, Scudiery D, et al. A phase II trial of PEG-L-asparaginase in the treatment of non-Hodgkins lymphoma. Invest New Drugs 1990; 8: 125–30

    PubMed  CAS  Article  Google Scholar 

  68. Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343: 1673–80

    PubMed  CAS  Article  Google Scholar 

  69. Glue P, Fang JW, Rouzier-Panis R, et al. Pegylated interferon-alpha2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Hepatitis C Intervention Therapy Group. Clin Pharmacol Ther 2000; 68: 556–67

    PubMed  CAS  Article  Google Scholar 

  70. Yasuda Y, Fujita T, Takakura Y, et al. Biochemical and biopharmaceutical properties of macromolecular conjugates of uricase with dextran and polyethylene glycol. Chem Pharm Bull (Tokyo) 1990; 38: 2053–6

    CAS  Article  Google Scholar 

  71. Muller AF, Kopchick JJ, Flyvbjerg A, et al. Clinical review 166: Growth hormone receptor antagonists. J Clin Endocrinol Metab 2004; 89: 1503–11

    PubMed  CAS  Article  Google Scholar 

  72. Kramer GC. Counterintuitive red blood cell substitute: polyethylene glycol-modified human hemoglobin. Crit Care Med 2003; 31: 1882–4

    PubMed  CAS  Article  Google Scholar 

  73. Maher S, Toomey D, Condron C, et al. Activation-induced cell death: the controversial role of Fas and Fas ligand in immune privilege and tumour counterattack. Immunol Cell Biol 2002; 80: 131–7

    PubMed  CAS  Article  Google Scholar 

  74. Nagata S. Apoptosis by death factor. Cell 1997; 88: 355–65

    PubMed  CAS  Article  Google Scholar 

  75. Daniel PT, Scholz C, Westermann J, et al. Dendritic cells prevent CD95 mediated T lymphocyte death through costimulatory signals. Adv Exp Med Biol 1998; 451: 173–7

    PubMed  CAS  Article  Google Scholar 

  76. Restifo NP. Not so Fas: re-evaluating the mechanisms of immune privilege and tumor escape. Nat Med 2000; 6: 493–5

    PubMed  CAS  Article  Google Scholar 

  77. Walker PR, Saas P, Dietrich PY. Role of Fas ligand (CD95L) in immune escape: the tumor cell strikes back. J Immunol 1997; 158: 4521–4

    PubMed  CAS  Google Scholar 

  78. von Bernstorff W, Spanjaard RA, Chan AK, et al. Pancreatic cancer cells can evade immune surveillance via nonfunctional Fas (APO-1/CD95) receptors and aberrant expression of functional Fas ligand. Surgery 1999; 125: 73–84

    Article  Google Scholar 

  79. Strand S, Hofmann WJ, Hug H, et al. Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells: a mechanism of immune evasion? Nat Med 1996; 2: 1361–6

    PubMed  CAS  Article  Google Scholar 

  80. O’Connell J, O’sullivan GC, Collins JK, et al. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 1996; 184: 1075–82

    PubMed  Article  Google Scholar 

  81. Niehans GA, Brunner T, Frizelle SP, et al. Human lung carcinomas express Fas ligand. Cancer Res 1997; 57: 1007–12

    PubMed  CAS  Google Scholar 

  82. Hahne M, Rimoldi D, Schroter M, et al. Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 1996; 274: 1363–6

    PubMed  CAS  Article  Google Scholar 

  83. Friesen C, Fulda S, Debatin KM. Cytotoxic drugs and the CD95 pathway. Leukemia 1999; 13: 1854–8

    PubMed  CAS  Article  Google Scholar 

  84. Rihova B, Strohalm J, Hoste K, et al. Immunoprotective therapy with targeted anticancer drugs. Macromol Symp 2001; 172: 21–8

    CAS  Article  Google Scholar 

  85. Ringsdorf H. Structure and properties of pharmacologically active polymers. J Polym Sci Symp 1975; 51: 135–53

    CAS  Article  Google Scholar 

  86. Duncan R. Drug-polymer conjugates: potential for improved chemotherapy. Anticancer Drugs 1992; 3: 175–210

    PubMed  CAS  Article  Google Scholar 

  87. Jain RK. The next frontier of molecular medicine: delivery of therapeutics. Nat Med 1998; 4: 655–7

    PubMed  CAS  Article  Google Scholar 

  88. Petrak K. Essential properties of drug-targeting delivery systems. Drug Discov Today 2005; 10: 1667–73

    PubMed  CAS  Article  Google Scholar 

  89. Takakura Y, Takagi A, Hashida M, et al. Disposition and tumor localization of mitomycin C-dextran conjugates in mice. Pharm Res 1987; 4: 293–300

    PubMed  CAS  Article  Google Scholar 

  90. Veronese FM, Morpurgo M. Bioconjugation in pharmaceutical chemistry. Farmaco 1999; 54: 497–516

    PubMed  CAS  Article  Google Scholar 

  91. Kawaguchi T, Asakawa H, Tashiro Y, et al. Stability, specific binding activity, and plasma concentration in mice of an oligodeoxynucleotide modified at 5′-terminal with polyethylene glycol). Biol Pharm Bull 1995; 18: 474–6

    PubMed  CAS  Article  Google Scholar 

  92. Herman S, Hooftman G, Schacht E. Poly (ethylene glycol) with reactive endgroups: I - modification of proteins. J Bioact Compat Polym 1995; 10: 145–87

    CAS  Google Scholar 

  93. Veronese FM. Peptide and protein PEGylation: a review of problems and solutions. Biomaterials 2001; 22: 405–17

    PubMed  CAS  Article  Google Scholar 

  94. Sato H. Enzymatic procedure for site-specific pegylation of proteins. Adv Drug Deliv Rev 2002; 54: 487–504

    PubMed  CAS  Article  Google Scholar 

  95. Jaschke A, Furste JP, Nordhoff E, et al. Synthesis and properties of oligodeoxyribonucleotide-polyethylene glycol conjugates. Nucleic Acids Res 1994; 22: 4810–7

    PubMed  CAS  Article  Google Scholar 

  96. Tarasow TM, Tinnermeier D, Zyzniewski C. Characterization of oligodeoxyribonucleotide-polyethylene glycol conjugates by electrospray mass spectrometry. Bioconjug Chem 1997; 8: 89–93

    PubMed  CAS  Article  Google Scholar 

  97. Greish K, Fang J, Inutsuka T, et al. Macromolecular therapeutics: advantages and prospects with special emphasis on solid tumour targeting. Clin Pharmacokinet 2003; 42: 1089–105

    PubMed  CAS  Article  Google Scholar 

  98. Caliceti P, Monfardini C, Sartore L, et al. Preparation and properties of monomethoxy poly(ethylene glycol) doxorubicin conjugates linked by an amino acid or a peptide as spacer. Farmaco 1993; 48: 919–32

    PubMed  CAS  Google Scholar 

  99. Levy Y, Hershfield MS, Fernandez-Mejia C, et al. Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase. J Pediatr 1988; 113: 312–7

    PubMed  CAS  Article  Google Scholar 

  100. Graham ML. Pegaspargase: a review of clinical studies. Adv Drug Deliv Rev 2003; 55: 1293–302

    PubMed  CAS  Article  Google Scholar 

  101. Reddy KR, Modi MW, Pedder S. Use of peginterferon a-2a (40 KD) (Pegasys®) for the treatment of hepatitis C. Adv Drug Deliv Rev 2002; 54: 571–86

    Article  Google Scholar 

  102. Wang YS, Youngster S, Grace M, et al. Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Adv Drug Deliv Rev 2002; 54: 547–70

    PubMed  CAS  Article  Google Scholar 

  103. Bukowski R, Ernstoff MS, Gore ME, et al. Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study. J Clin Oncol 2002; 20: 3841–9

    PubMed  CAS  Article  Google Scholar 

  104. Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebo-controlled, phase III study of filgrastim in remission induction and consolidation therapy for adults with de novo acute myeloid leukemia. The International Acute Myeloid Leukemia Study Group. Blood 1997; 90: 4710–8

    PubMed  CAS  Google Scholar 

  105. Holmes FA, Jones SE, O’shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol 2002; 13: 903–9

    PubMed  CAS  Article  Google Scholar 

  106. Kinstler O, Molineux G, Treuheit M, et al. Mono-N-terminal poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev 2002; 54: 477–85

    PubMed  CAS  Article  Google Scholar 

  107. Vellard M. The enzyme as drug: application of enzymes as pharmaceuticals. Curr Opin Biotechnol 2003; 14: 1–7

    Article  CAS  Google Scholar 

  108. Vicent MJ, Duncan R. Polymer conjugates: nanosized medicines for treating cancer. Trends Biotechnol 2006; 24: 39–47

    PubMed  CAS  Article  Google Scholar 

  109. Clark R, Olson K, Fuh G, et al. Long-acting growth hormones produced by conjugation with polyethylene glycol. J Biol Chem 1996; 271: 21969–77

    PubMed  CAS  Article  Google Scholar 

  110. Drake WM, Trainer PJ. Clinical use of pegvisomant for the treatment of acromegaly. Treat Endocrinol 2003; 2: 369–74

    PubMed  CAS  Article  Google Scholar 

  111. Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterology 2005; 129: 807–18

    PubMed  CAS  Article  Google Scholar 

  112. Chapman AP, Antoniw P, Spitali M, et al. Therapeutic antibody fragments with prolonged in vivo half-lives. Nat Biotechnol 1999; 17: 780–3

    PubMed  CAS  Article  Google Scholar 

  113. Conover CD, Linberg R, Gilbert CW, et al. Effect of polyethylene glycol conjugated bovine hemoglobin in both top-load and exchange transfusion rat models. Artif Organs 1997; 21: 1066–75

    PubMed  CAS  Article  Google Scholar 

  114. Bomalaski JS, Holtsberg FW, Ensor CM, et al. Uricase formulated with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies. J Rheumatol 2002; 29: 1942–9

    PubMed  CAS  Google Scholar 

  115. Greenwald RB, Choe YH, McGuire J, et al. Effective drug delivery by PEGylated drug conjugates. Adv Drug Deliv Rev 2003; 55: 217–50

    PubMed  CAS  Article  Google Scholar 

  116. Greenwald RB, Gilbert CW, Pendri A, et al. Drug delivery systems: water soluble taxol 2′-poly(ethylene glycol) ester prodrugs-design and in vivo effectiveness. J Med Chem 1996; 39: 424–31

    PubMed  CAS  Article  Google Scholar 

  117. Eyetech Study Group. Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina 2002; 22: 143–52

    Article  Google Scholar 

  118. Filbey JA, Charles SA. Shellac to pegylation: 2500 years of polymers in controlled release drug delivery. Drug Delivery Technology 2005; 5: 65–9

    Google Scholar 

  119. Haffner ME. The Food and Drug Administration’s Office of Orphan Products Development: incentives, grants, and special designations speed therapies for orphan diseases. Retina 2005; 25: S89–90

    PubMed  Article  Google Scholar 

  120. Mashburn LT, Wriston Jr JC. Tumor inhibitory effect of L-asparaginase from escherichia coli. Arch Biochem Biophys 1964; 105: 450–2

    PubMed  CAS  Article  Google Scholar 

  121. Soares AL, Guimaraes GM, Polakiewicz B, et al. Effects of polyethylene glycol attachment on physicochemical and biological stability of E. coli L-asparaginase. Int J Pharm 2002; 237: 163–70

    PubMed  CAS  Article  Google Scholar 

  122. Sawa T, Sahoo SK, Maeda H. Water-soluble polymer therapeutics with a special emphasis on cancer chemotherapy. In: Arshady R, editor. Polymeric biomaterials, the PBM series, volume 1: introduction to polymeric biomaterials. London: Citus Books, 2003: 233–61

    Google Scholar 

  123. Glue P, Rouzier-Panis R, Raffanel C, et al. A dose-ranging study of pegylated interferon alfa-2b and ribavirin in chronic hepatitis C. The Hepatitis C Intervention Therapy Group. Hepatology 2000; 32: 647–53

    PubMed  CAS  Article  Google Scholar 

  124. Bowen S, Tare N, Inoue T, et al. Relationship between molecular mass and duration of activity of polyethylene glycol conjugated granulocyte colony-stimulating factor mutein. Exp Hematol 1999; 27: 425–32

    PubMed  CAS  Article  Google Scholar 

  125. Satake-Ishikawa R, Ishikawa M, Okada Y, et al. Chemical modification of recombinant human granulocyte colony-stimulating factor by polyethylene glycol increases its biological activity in vivo. Cell Struct Funct 1992; 17: 157–60

    PubMed  CAS  Article  Google Scholar 

  126. Paisley AN, Drake WM. Treatment of pituitary tumors: pegvisomant. Endocrine 2005; 28: 111–4

    PubMed  CAS  Article  Google Scholar 

  127. Nucci ML, Olejarczyk J, Abuchowski A. Immunogenicity of polyethylene glycol-modified superoxide dismutase and catalase. J Free Radic Biol Med 1986; 2: 321–5

    PubMed  CAS  Article  Google Scholar 

  128. Pyatak PS, Abuchowski A, Davis FF. Preparation of a polyethylene glycol: superoxide dismutase adduct, and an examination of its blood circulation life and anti-inflammatory activity. Res Commun Chem Pathol Pharmacol 1980; 29: 113–27

    PubMed  CAS  Google Scholar 

  129. Muizelaar JP. Clinical trials with Dismutec (pegorgotein; polyethylene glycol-conjugated superoxide dismutase; PEG-SOD) in the treatment of severe closed head injury. Adv Exp Med Biol 1994; 366: 389–400

    PubMed  CAS  Article  Google Scholar 

  130. Muizelaar JP, Marmarou A, Young HF, et al. Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a phase II trial. J Neurosurg 1993; 78: 375–82

    PubMed  CAS  Article  Google Scholar 

  131. Feldmann M, Maini RN. Discovery of TNF-alpha as a therapeutic target in rheumatoid arthritis: preclinical and clinical studies. Joint Bone Spine 2002; 69: 12–8

    PubMed  Article  Google Scholar 

  132. Sandborn WJ. Strategies for targeting tumour necrosis factor in IBD. Best Pract Res Clin Gastroenterol 2003; 17: 105–17

    PubMed  CAS  Article  Google Scholar 

  133. Beutler E, Gelbart T. Glucocerebrosidase (Gaucher disease). Hum Mutat 1996; 8: 207–13

    PubMed  CAS  Article  Google Scholar 

  134. Linberg R, Conover CD, Shum KL, et al. Increased tissue oxygenation and enhanced radiation sensitivity of solid tumors in rodents following polyethylene glycol conjugated bovine hemoglobin administration. In Vivo 1998; 12: 167–73

    PubMed  CAS  Google Scholar 

  135. Davis S, Park YK, Abuchowski A, et al. Hypouricaemic effect of polyethyleneglycol modified urate oxidase. Lancet 1981; II: 281–3

    Article  Google Scholar 

  136. Lerchen HG. Camptothecin antitumor agents. IDrugs 1999; 2: 896–906

    PubMed  CAS  Google Scholar 

  137. Helene C. The anti-gene strategy: control of gene expression by triplex-forming-oligonucleotides. Anticancer Drug Des 1991; 6: 569–84

    PubMed  CAS  Google Scholar 

  138. Gold L. Oligonucleotides as research, diagnostic, and therapeutic agents. J Biol Chem 1995; 270: 13581–4

    PubMed  CAS  Google Scholar 

  139. Langer CJ. CT-2103: a novel macromolecular taxane with potential advantages compared with conventional taxanes. Clin Lung Cancer 2004; 6 Suppl. 2: S85–8

    PubMed  CAS  Article  Google Scholar 

  140. Siddiqui MA, Keating GM. Pegaptanib: in exudative age-related macular degeneration. Drugs 2005; 65: 1571–7

    PubMed  CAS  Article  Google Scholar 

  141. Fraunfelder FW. Pegaptanib for wet macular degeneration. Drugs Today (Barc) 2005; 41: 703–9

    CAS  Article  Google Scholar 

  142. Luo Y, Prestwich GD. Cancer-targeted polymeric drugs. Curr Cancer Drug Targets 2002; 2: 209–26

    PubMed  CAS  Article  Google Scholar 

  143. Yokoyama M. Drug targeting with nano-sized carrier systems. J Artif Organs 2005; 8: 77–84

    PubMed  CAS  Article  Google Scholar 

  144. Maeda H, Seymour LW, Miyamoto Y. Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. Bioconjug Chem 1992; 3: 351–62

    PubMed  CAS  Article  Google Scholar 

  145. Torchilin VP. Drug targeting. Eur J Pharm Sci 2000; 11 Suppl. 2: S81–91

    PubMed  CAS  Article  Google Scholar 

  146. Au JL, Jang SH, Zheng J, et al. Determinants of drug delivery and transport to solid tumors. J Control Release 2001; 74: 31–46

    PubMed  CAS  Article  Google Scholar 

  147. Langer R. Drug delivery and targeting. Nature 1998; 392: 5–10

    PubMed  CAS  Google Scholar 

  148. Modi S, Jain JP, Kumar N. Polymer-drug conjugates: recent development for anticancer drugs. CRIPS 2004; 5(2): 2–8

    Google Scholar 

  149. Monsky WL, Fukumura D, Gohongi T, et al. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res 1999; 59: 4129–35

    PubMed  CAS  Google Scholar 

  150. Hobbs SK, Monsky WL, Yuan F, et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci U S A 1998; 95: 4607–12

    PubMed  CAS  Article  Google Scholar 

  151. Yuan F, Salehi HA, Boucher Y, et al. Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res 1994; 54: 4564–8

    PubMed  CAS  Google Scholar 

  152. Dellian M, Witwer BP, Salehi HA, et al. Quantitation and physiological characterization of angiogenic vessels in mice: effect of basic fibroblast growth factor, vascular endothelial growth factor/vascular permeability factor, and host microenvironment. Am J Pathol 1996; 149: 59–71

    PubMed  CAS  Google Scholar 

  153. Maeda H, Fang J, Inutsuka T, et al. Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol 2003; 3: 319–28

    PubMed  CAS  Article  Google Scholar 

  154. Muggia FM. Doxorubicin-polymer conjugates: further demonstration of the concept of enhanced permeability and retention. Clin Cancer Res 1999; 5: 7–8

    PubMed  CAS  Google Scholar 

  155. Duncan R. Polymer conjugates for tumour targeting and intra-cytoplasmic delivery. The EPR effect as a common gateway? Pharm Sci Technol Today 1999; 2: 441–9

    CAS  Google Scholar 

  156. Fang J, Sawa T, Maeda H. Factors and mechanism of ‘EPR’ effect and the enhanced antitumor effects of macromolecular drugs including SMANCS. Adv Exp Med Biol 2003; 519: 29–49

    PubMed  CAS  Article  Google Scholar 

  157. Gleave ME, Coupland D, Drachenberg D, et al. Ability of serum prostate-specific antigen levels to predict normal bone scans in patients with newly diagnosed prostate cancer. Urology 1996; 47: 708–12

    PubMed  CAS  Article  Google Scholar 

  158. Garzotto M, Hudson RG, Peters L, et al. Predictive modeling for the presence of prostate carcinoma using clinical, laboratory, and ultrasound parameters in patients with prostate specific antigen levels < or = 10 ng/mL. Cancer 2003; 98: 1417–22

    PubMed  Article  Google Scholar 

  159. Caplan A, Kratz A. Prostate-specific antigen and the early diagnosis of prostate cancer. Am J Clin Pathol 2002; 117 Suppl.: S104–8

    PubMed  Google Scholar 

  160. Sahoo SK, Labhasetwar V. Enhanced antiproliferative activity of transferrin-conjugated paclitaxel-loaded nanoparticles is mediated via sustained intracellular drug retention. Mol Pharm 2005; 2: 373–83

    PubMed  CAS  Article  Google Scholar 

  161. Sahoo SK, Ma W, Labhasetwar V. Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer 2004; 112: 335–40

    PubMed  CAS  Article  Google Scholar 

  162. Lamprecht A, Ubrich N, Yamamoto H, et al. Biodegradable nanoparticles for targeted drug delivery in treatment of inflammatory bowel disease. J Pharmacol Exp Ther 2001; 299: 775–81

    PubMed  CAS  Google Scholar 

  163. Scherer F, Anton M, Schillinger U, et al. Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo. Gene Ther 2002; 9: 102–9

    PubMed  CAS  Article  Google Scholar 

  164. Thorpe PE. Vascular targeting agents as cancer therapeutics. Clin Cancer Res 2004; 10: 415–27

    PubMed  Article  Google Scholar 

  165. Fonsatti E, Altomonte M, Arslan P, et al. Endoglin (CD105): a target for anti-angiogenetic cancer therapy. Curr Drug Targets 2003; 4: 291–6

    PubMed  CAS  Article  Google Scholar 

  166. Molema G, Meijer DK, de Leij LF. Tumor vasculature targeted therapies: getting the players organized. Biochem Pharmacol 1998; 55: 1939–45

    PubMed  CAS  Article  Google Scholar 

  167. Stevanovic S. Identification of tumour-associated T-cell epitopes for vaccine development. Nat Rev Cancer 2002; 2: 514–20

    PubMed  CAS  Article  Google Scholar 

  168. Juretic A, Spagnoli GC, Schultz-Thater E, et al. Cancer/testis tumour-associated antigens: immunohistochemical detection with monoclonal antibodies. Lancet Oncol 2003; 4: 104–9

    PubMed  CAS  Article  Google Scholar 

  169. Vasir JK, Labhasetwar V. Targeted drug delivery in cancer therapy. Technol Cancer Res Treat 2005; 4: 363–74

    PubMed  CAS  Google Scholar 

  170. Schally AV, Nagy A. Chemotherapy targeted to cancers through tumoral hormone receptors. Trends Endocrinol Metab 2004; 15: 300–10

    PubMed  CAS  Article  Google Scholar 

  171. Weiner LM. Fully human therapeutic monoclonal antibodies. J Immunother 2006; 29: 1–9

    PubMed  CAS  Article  Google Scholar 

  172. Trail PA, Willner D, Lasch SJ, et al. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science 1993; 261: 212–5

    PubMed  CAS  Article  Google Scholar 

  173. Okamoto K, Yamaguchi T, Otsuji E, et al. Targeted chemotherapy in mice with peritoneally disseminated gastric cancer using monoclonal antibody-drug conjugate. Cancer Lett 1998; 122: 231–6

    PubMed  CAS  Article  Google Scholar 

  174. Remsen LG, Trail PA, Hellstrom I, et al. Enhanced delivery improves the efficacy of a tumor-specific doxorubicin immunoconjugate in a human brain tumor xenograft model. Neurosurgery 2000; 46: 704–9

    PubMed  CAS  Article  Google Scholar 

  175. Wakai Y, Matsui J, Koizumi K, et al. Effective cancer targeting using an anti-tumor tissue vascular endothelium-specific monoclonal antibody (TES-23). Jpn J Cancer Res 2000; 91: 1319–25

    PubMed  CAS  Article  Google Scholar 

  176. Sartore L, Caliceti P, Schiavon O, et al. Accurate evaluation method of the polymer content in monomethoxy(polyethylene glycol) modified proteins based on amino acid analysis. Appl Biochem Biotechnol 1991; 31: 213–22

    PubMed  CAS  Article  Google Scholar 

  177. Snyder SL, Sobocinski PZ. An improved 2,4,6-trinitrobenzene-sulfonic acid method for the determination of amines. Anal Biochem 1975; 64: 284–8

    PubMed  CAS  Article  Google Scholar 

  178. Habeeb AF. Determination of free amino groups in proteins by trinitrobenzenesulfonic acid. Anal Biochem 1966; 14: 328–36

    PubMed  CAS  Article  Google Scholar 

  179. Choe YH, Conover CD, Wu D, et al. Anticancer drug delivery systems: multi-loaded N4-acyl poly(ethylene glycol) prodrugs of ara-C: II. efficacy in ascites and solid tumors. J Control Release 2002; 79: 55–70

    PubMed  CAS  Article  Google Scholar 

  180. Monfardini C, Schiavon O, Caliceti P, et al. A branched monomethoxypoly(ethylene glycol) for protein modification. Bioconjug Chem 1995; 6: 62–9

    PubMed  CAS  Article  Google Scholar 

  181. Ono K, Kai Y, Maeda H, et al. Selective synthesis of 2,4-bis(O-methoxypolyethylene glycol)-6-chloro-s-triazine as a protein modifier. J Biomater Sci Polym Ed 1991; 2: 61–5

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgements

There is no conflict of interest that would prejudice the impartiality of this review. Sanjeeb K. Sahoo would like to thank the Director, Institute of Life Sciences for providing all the necessary facilities and Suphiya Parveen would like to thank the Department of Biotechnology, Government of India for the Junior Research Fellowship.

Author information

Affiliations

  1. Nanomedicine Laboratory, Institute of Life Sciences, Nalco Square, Chandrasekharpur, Bhubaneswar, Orissa, 751 023, India

    Suphiya Parveen &  Sanjeeb K. Sahoo

Authors
  1. Suphiya Parveen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjeeb K. Sahoo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sanjeeb K. Sahoo.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Parveen, S., Sahoo, S.K. Nanomedicine. Clin Pharmacokinet 45, 965–988 (2006). https://doi.org/10.2165/00003088-200645100-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200645100-00002

Keywords

  • Acromegaly
  • Enzyme Replacement Therapy
  • Pegvisomant
  • Pegaptanib
  • Pegaspargase