PEG: a useful technology in anticancer therapy

  • Anna Mero
  • Gianfranco Pasut
  • Francesco M. Veronese
Part of the Milestones in Drug Therapy book series (MDT)


Cancer chemotherapy dates back to the 1940s with the first use of nitrogen mustards and antifolate drugs. The use of small molecule and bio pharmaceutical drugs is today the acceptable approach to cancer treatment in both ambulatory and in patient care. Drug delivery of these drugs has given rise to safer and more efficacious options. Today, the use of polymers for sustained and targeted delivery has allowed oncologists to deal with the earlier limitations of chemotherapy. In this chapter the focus is on polymer conjugation of anticancer drugs, such as high molecular weight proteins and low molecular weight compounds. Examples will be presented to demonstrate an increase in the pharmacological therapeutic index by targeting the drug molecules to the diseased sites with corresponding reduction in drug related side effects. The focus will be on the attachment of polyethylene glycol (PEG) to oncolytic drugs, a process referred to as PEGylation. This technology has been completely validated in the area of protein modification, but is very much in its infancy in the modification of small molecular weight drugs. However, increasing and encouraging efforts have recently been made and will be presented. This chapter will also discuss recent achievements in PEGylation processes with a particular emphasis on the application of PEG to non-conventional therapies such as oxidation therapy, photodynamic therapy and radiopharmaceutical therapy.


Acute Lymphoblastic Leukemia Chronic Myeloid Leukemia Imatinib Mesylate Anticancer Therapy Arginine Deiminase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Gilman, A. (1946) The biological actions and therapeutic applications of the B-chloroethyl amines and sulphides. Science 103, 409–436.CrossRefPubMedGoogle Scholar
  2. 2.
    Chabner, B.A., Roberts, T.G. (2005) Chemotherapy and the war on cancer. Nat. Rev. Cancer. 5, 65–72.CrossRefPubMedGoogle Scholar
  3. 3.
    Druker, B.J. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037.CrossRefPubMedGoogle Scholar
  4. 4.
    Kantarjian, H. (2002) Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N. Engl. J. Med. 346, 645–652.CrossRefPubMedGoogle Scholar
  5. 5.
    Ringsdorf, H. (1975) Structure and properties of pharmacologically active polymers. J. Polym. Sci. Symp. 51, 135–153.CrossRefGoogle Scholar
  6. 6.
    Matsumura, Y., Maeda, H. (1986) A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumour agent, SMANCS. Cancer Res. 6, 6387–6392.Google Scholar
  7. 7.
    Maeda, H., Wu, J., Sawa, T., Matsumura, Y., Hori, K. (2000) Tumour vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65, 271–284.CrossRefPubMedGoogle Scholar
  8. 8.
    Hawkins, M.J., Soon-Shiong, P., Desai, N. (2008) Protein nanoparticles as drug carriers in clinical medicine. Adv. Drug Deliv. Rev. 60, 876–885.CrossRefPubMedGoogle Scholar
  9. 9.
    Singer, J.W., Shaffer, S., Baker, B., Bernareggi, A., Stromatt, S., Nienstedt, D., Besman, M. (2005) Paclitaxel poliglumex (XYOTAX; CT-2103): an intracellularly targeted taxane. Anticancer Drugs 16, 243–254.CrossRefPubMedGoogle Scholar
  10. 10.
    Pasut, G., Veronese, F.M. (2007) Progress in polymer science, Polymer-drug conjugation, recent achievements and general strategies. Progress in Polymer Science 32, 933–961.CrossRefGoogle Scholar
  11. 11.
    Rowinsky, E.K., Rizzo, J., Ochoa, L., Takimoto, C.H., Forouzesh, B., Schwartz, G. (2003) A phase I and pharmacokinetic study of pegylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies. J. Clin. Oncol. 21, 148–157.CrossRefPubMedGoogle Scholar
  12. 12.
    Scott, L.C., Yao, J.C., Benson A.B., Thomas, A.L., Falk, S., Mena, R.R., Picus, J., Wright, J., Mulcahy, M.F., Ajani, J.A., Evans, T.R. (2008) A phase II study of pegylated-camptothecin (peg-amotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma. Cancer Chemother. Pharmacol. 63, 363–370.CrossRefPubMedGoogle Scholar
  13. 13.
    Berna, M., Dalzoppo, D., Pasut, G., Manunta, M., Izzo, L., Jones, A.T., Duncan, R., Veronese, F.M. (2006) Novel monodisperse PEG-dendrons as new tools for targeted drug delivery: synthesis, characterization and cellular uptake. Biomacromolecules 7, 146–153.CrossRefPubMedGoogle Scholar
  14. 14.
    Eldon, M.A., Staschen CM., Viegas, T., Bentley, M. (2007) NKTR-102, a novel PEGylated-irinotecan conjugate, results in sustained tumor growth inhibition in mouse models of human colorectal and lung tumors that is associated with increased and sustained tumor SN38 exposure. 2007 AACR-NCI-EORTC International Conference, San Francisco, Poster C157.Google Scholar
  15. 15.
    Von Hoff, D.D., Jameson, G.S., Borad, M.J., Rosen, L.S., Utz, J., Basche, M., Alemany, C., Dhar, S., Acosta, L., Barker, T., Walling, J., Hamm, J.T. (2008) First phase I trial of NKTR-102 (PEG-Irinotecan) reveals early evidence of broad anti-tumour activity in three different schedules. 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Geneva, Switzerland, Poster 595.Google Scholar
  16. 16.
    Zhao, H., Rubio, B., Sapra, P., Wu, D., Reddy, P., Sai, P., Martinez, A., Gao, Y., Lozanguiez, Y., Longley, C., Greenberger, L.M., Horak, I.D. (2008) Novel prodrugs of SN38 using multiarm poly(ethylene glycol) linkers. Bioconjug Chem. 19, 849–859.CrossRefPubMedGoogle Scholar
  17. 17.
    Sapra, P., Zhao, H., Mehlig, M., Malaby, J., Kraft, P., Longley, C., Greenberger, L.M., Horak, I.D. (2008) Novel Delivery of SN38 Markedly Inhibits Tumour Growth in Xenografts, Including a Camptothecin-11-Refractory Model. Clin. Can. Res. 14, 1888–1896.CrossRefGoogle Scholar
  18. 18.
    Guo, Z., Wheler, J.J., Naing, A., Mani, S., Goel, S., Mulcahy, M., Gamza, F., Longley, C., Buchbinder, A., Kurzrock, R. (2008) Clinical pharmacokinetics (PK) of EZN-2208, a novel anticancer agent, in patients (pts) with advanced malignancies: A phase I, first-in-human, dose-escalation study. J. Clin. Oncol. 26 (abstr 2556).Google Scholar
  19. 19.
    Wolff, R., Routt, S., Hartsook, R., Riggs, J., Zhang W., Persson, H., Johnson, R. (2008) NKTR-105, a novel PEGylated-docetaxel demonstrates superior anti-tumor activity compared to docetaxel in human non-small cell lung and colon cancer xenografts. 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Geneva, Switzerland, Poster 448.Google Scholar
  20. 20.
    Greco, F., Vicent, M.J. (2008) Polymer-drug conjugates: current status and future trends, Front Biosci. 13, 2744–2756.CrossRefPubMedGoogle Scholar
  21. 21.
    Dharap, S.S., Wang, Y., Chandna, P., Khandare, J.J., Qiu, B., Gunaseelan, S., Sinko, P.J., Stein, S., Farmanfarmaian, A., Minko, T. (2005) Tumour-specific targeting of an anticancer drug delivery system by LHRH peptide, Proc. Natl. Acad. Sci. USA. 102, 12962–12967.CrossRefPubMedGoogle Scholar
  22. 22.
    Khandare, J.J., Chandna, P., Wang, Y., Pozharov, V.P., Minko, T. (2006) Novel polymeric prodrug with multivalent components for cancer therapy. J. Pharmacol. Exp. Ther. 317, 929–937.CrossRefPubMedGoogle Scholar
  23. 23.
    Nemunaitis, J., Cunningham, C., Senzer, N., Gray, M., Oldham, F., Pippen, J., Mennel, R., Eisenfeld, A. (2005) Phase I study of CT-2103, a polymer-conjugated paclitaxel, and carboplatin in patients with advanced solid tumours. Cancer Invest. 23, 671–676.CrossRefPubMedGoogle Scholar
  24. 24.
    Dipetrillo, T., Milas, L., Evans, D., Akerman, P., Ng, T., Miner, T., Cruff, D., Chauhan, B., Iannitti, D., Harrington, D., Safran, H. (2006) Paclitaxel poliglumex (PPX-xyotax) and concurrent radiation for esophageal and gastric cancer — A phase I study. Am. J. Clin. Oncol.-Canc. 29, 376–379.Google Scholar
  25. 25.
    Santucci, L., Mencarelli, A., Renga, B., Pasut, G., Veronese, F.M., Zacheo, A., Germani, A., Fiorucci, S. (2006) Nitric oxide modulates proapoptotic and antiapoptotic properties of chemotherapy agents: the case of NO-pegylated epirubicin. Faseb J. 20, 765–767.PubMedGoogle Scholar
  26. 26.
    Fogli, S., Nieri, P., Breschi, M.C. (2004) The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage. Faseb J. 18, 664–675.CrossRefPubMedGoogle Scholar
  27. 27.
    Cantucci, L., Mencarelli, A., Renga, B., Ceccobelli, D., Pasut, G., Veronese, F.M., Distrutti, E., Fiorucci, S. (2007) Cardiac safety and antitumoral activity of anew nitric oxide derivative of pegy-lated epirubicin in mice. Anticancer Drugs. 18, 1081–1091.CrossRefGoogle Scholar
  28. 28.
    Pasut, G., Canal, F., Dalla Via, L., Arpicco, S., Veronese, F.M., Schiavon, O. (2008) Antitumoral activity of PEG-gemcitabine prodrugs targeted by folic acid. Journal Control. Rel. 127, 239–248.CrossRefGoogle Scholar
  29. 29.
    Vellard, M. (2003) The enzymes as a drug: application of enzymes as pharmaceuticals. Curr. Opin. Biotechnol. 14, 444–450.CrossRefPubMedGoogle Scholar
  30. 30.
    Abuchowski, A., Van Es, T., Palczuk, N.C., McCoy, J.R., Davis, F.F. (1 979) Treatment of L5178Y tumour-bearing BDF1 mice with a nonimmunogenic L-glutaminase-L-asparaginase. Cancer Treat. Rep. 63, 1127–1132.Google Scholar
  31. 31.
    Abuchowski, A., Kazo, G.M., Verhoest, J.R., Van Es, T., Kafkewitz, D., Nucci, M.L., Viau, A.T., Davis, F.F. (1984) Cancer therapy with chemically modified enzymes. I. Antitumour properties of polyethylene glycol-asparaginase conjugates. Cancer Biochem. Biophys. 7, 175–186.PubMedGoogle Scholar
  32. 32.
    Kurtzberg, J. (2000) Cancer Medicines. 5th ed. Gansler T., Decker Inc, Canada.Google Scholar
  33. 33.
    Dinndorf, P.A., Gootenberg, J., Cohen, M.H., Keegan, P., Pazdur, R. (2007) FDA drug approval summary: Pegaspargase (Oncaspar®) for the first-line treatment of children with acute lym phoblastic leukemia (ALL). The Oncologist 12, 991–998.CrossRefPubMedGoogle Scholar
  34. 34.
    Apostolidou, E., Swords, R., Alvarado, Y., Giles, F.J. (2007) Treatment of acute lymphoblastic leukemia (ALL): a new era. Drugs 67, 2153–2171.CrossRefPubMedGoogle Scholar
  35. 35.
    Sherman, M.R., Saifer, M.G., Perez-Ruiz, F. (2008) PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv. Drug Deliv. Rev. 60, 59–68.CrossRefPubMedGoogle Scholar
  36. 36.
    Armstrong, J.K., Hempel, G., Koling, S., Chan, L.S., Fisher, T., Meiselman, H.J., Garratty, G. (2007) Antibody against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 110, 103–111.CrossRefPubMedGoogle Scholar
  37. 37.
    Sugimura, K., Ohno, T., Kusuyama, T., Azuma, I. (1992) High sensitivity of human melanoma cell lines to the growth inhibitory activity of mycoplasmal arginine deiminase in vitro. MelanomaRes. 2, 191–196.Google Scholar
  38. 38.
    Cheng, P.N., Leung, Y.C., Lo, W.H., Tsui, S.M., Lam, K.C. (2005) Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: arginase as a potential drug candidate for hepatocellular carcinoma. Cancer Lett. 224, 67–80.PubMedGoogle Scholar
  39. 39.
    Gong, H., Zolzer, F., von Recklinghausen, G., Havers, W., Schweigerer, L. (2000) Arginine deim-inase inhibits proliferation of human leukemia cells more potently than asparaginase by inducing cell cycle arrest and apoptosis. Leukemia 14, 826–829.CrossRefPubMedGoogle Scholar
  40. 40.
    Holtsberg, F.W., Ensor, CM., Steiner, M.R., Bomalaski, J.S., Clark, M.A. (2002) Polyethylene glycol) (PEG) conjugated arginine deiminase: Effects of PEG formulations on its pharmacological properties. J. Control. Rel. 80, 259–271.CrossRefGoogle Scholar
  41. 41.
    Izzo, E, Marra, P., Beneduce, G., Castello, G., Vallone, P., De Rosa, V., Cremona, F., Ensor, C.M., Holtsberg, F.W., Bomalaski, J.S., Clark, M.A., Ng, C, Curley, S.A. (2004) PEGylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: Results from phase I/II studies. J. Clin. Oncol. 22, 1815–1822.CrossRefPubMedGoogle Scholar
  42. 42.
    Ascierto, P.A., Scala, S., Castello, G., Daponte, A., Simeone, E., Ottaiano, A. (2005) Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies. J. Clin. Oncol. 23, 7660–7668.CrossRefPubMedGoogle Scholar
  43. 43.
    Savoca, K.V., Davis, F.F., Van Es, T., McCoy, J.R., Palczuk, N.C (1984) Cancer therapy with chemically modified enzymes. II. The therapeutic effectiveness of arginase, and arginase modified by the covalent attachment of polyethylene glycol, on the taper liver tumour and the L5178Y murine leukaemia. Cancer Biochem. Biophys. 7, 261–268.PubMedGoogle Scholar
  44. 44.
    Tsui, S.M., Lam, W.M., Lam, T.L., Chong, H.C., So, P.K., Kwok, S.Y., Arnold, S., Cheng, P.N.M., Wheatley, D.N., Lo, W.H., Leung, Y.C. (2009) PEGylated derivatives of recombinant human arginase I (rhArgl) for sustained in vivo activity in cancer therapy.l. Preparation and characterization. J. Cell Mol. Med. 9, 9–22.Google Scholar
  45. 45.
    Cheng, P.N., Lam, T., Lam, W, Tsui, S., Cheng, A.W., Lo, W., Leung, Y. (2007) Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Res. 67, 309–317.CrossRefPubMedGoogle Scholar
  46. 46.
    Yang, Z., Sun, X., Li, S., Tan, Y., Wang, X., Zhang, N., Yagi, S., Takakura, T., Kobayashi, Y., Takimoto, A., Yoshioka, T., Suginaka, A., Frenkel, E.P., Hoffman, R.M. (2004) Circulating half-life of PEGylated recombinant methioninase holoenzyme is highly dose dependent on cofactor pyridoxal-5-phosphate. Cancer Res. 64, 5775–5778.CrossRefPubMedGoogle Scholar
  47. 47.
    Yang, Z., Wang, J., Yoshioka, T., Li, B., Lu, Q., Li, S., Sun, X., Tan, Y., Yagi, S., Frenkel, E.P., Hoffman, R.M. (2004) Pharmacokinetics, methionine depletion, and antigenicity of recombinant methioninase in primates. Clin. Cancer Res. 10, 2131–2138.CrossRefPubMedGoogle Scholar
  48. 48.
    Yang, Z., Wang, J., Lu, Q., Xu, J., Kobayashi, Y., Takakura, T., Takimoto, A., Yoshioka, T., Lian, C, Chen, C, Zhang, D., Zhang, Y., Li, S., Sun, X., Tan, Y., Yagi, S., Frenkel, E.P., Hoffman, R.M. (2004) PEGylation confers greatly extended half-life and attenuated immunogenicity to recombinant methioninase in primates. Cancer Res. 64, 6673–6678.CrossRefPubMedGoogle Scholar
  49. 49.
    Fang, J., Seki, T., Maeda, H. (2009) Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv. Drug Deliv. Rev. 61, 290–302.CrossRefPubMedGoogle Scholar
  50. 50.
    Yoshikawa, T., Kokura, S., Tanaka, K., Naito, Y., Kondo, M. (1995) A novel cancer therapy based on oxygen radicals. Cancer Res. 55, 1617–1620.PubMedGoogle Scholar
  51. 51.
    Ben-Yoseph, O., Ross, B. D. (1994) oxidation therapy: the use of a reactive oxygen species generating enzyme system for tumour treatment. Br. J. Cancer 70, 1131–1135.PubMedGoogle Scholar
  52. 52.
    Sawa, T., Wu, J., Akaike, T., Maeda, H. (2002) Tumour-targeting chemotherapy by a xanthine oxi-dase-polymer conjugate that generates oxygen-free radicals in tumour tissue. Cancer Res. 60, 666–671.Google Scholar
  53. 53.
    Yagi, K. (1971) Reaction mechanism of D-amino acids oxidase. Adv. Enzymol. Relat. Areas Mol. Biol. 34, 41–78.Google Scholar
  54. 54.
    Fang, J., Nakamura, H., Deng, D.W., Akuta, T., Greish, K., Iyer, A.K., Maeda, H. (2008) Oxystress inducing antitumour therapeutics via targeted delivery of PEG-conjugated D-amino acid oxidase. Int. J. Cancer 122, 1135–1144.CrossRefPubMedGoogle Scholar
  55. 55.
    Fang, J., Sawa, T., Akaike, T., Akuta, T., Sahoo, S.K., Greish, K., Hamada, A., Maeda, H. (2003) In vivo antitumour activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumour. Cancer. Res. 63, 3567–3674.PubMedGoogle Scholar
  56. 56.
    Regehly, M., Greish, K., Rancan, E, Maeda, H., Bohm, F., Roder, B. (2007) Water-soluble polymer conjugates of ZnPP for photodynamic tumour therapy. Bioconjug. Chem. 18, 494–499.CrossRefPubMedGoogle Scholar
  57. 57.
    Iyer, A.K., Greish, K., Seki, T., Okazaki, S., Fang, J., Takeshita, K., Maeda, H. (2007) Polymeric micelles of zinc protoporphyrin for tumour targeted delivery based on EPR effect and singlet oxygen generation. J. Drug Target. 15, 496–506.CrossRefPubMedGoogle Scholar
  58. 58.
    Schiwon, K., Brauer, H.D., Gerlach, B., Muller, C.M., Montforts, F.P. (1994) Potential photosen-sitizers for photodynamic therapy. IV. Photophysical and photochemical properties of azapor-phirin and azachlorin derivatives. J. Photochem. Photobiol. B. Biol. 23, 239–243.CrossRefGoogle Scholar
  59. 59.
    Bettio, F., Canevari, M., Marzano, C, Bordin, F., Guiotto, A., Greco, F., Duncan, R., Veronese, F.M. (2006) Synthesis and biological in vitro evaluation of novel PEG-psoralen conjugates, Biomacromolecules 7, 3534–3541.CrossRefPubMedGoogle Scholar
  60. 60.
    Vaidya, A., Sun, Y., Feng, Y., Emerson, L., Jeong, E., Zheng-Rong L. (2008) Contrast-enhanced MRI-guided photodynamic cancer therapy with a pegylated bifunctional polymer conjugate. Pharm. Res., 25, 2002–2011.CrossRefPubMedGoogle Scholar
  61. 61.
    Wang, Y., Ye, F., Jeong, E.K., Sun, Y, Parker, D.L., Lu, Z.R. (2007) Non-invasive visualization of pharmacokinetics, biodistribution and tumour targeting of poly[N-(2-hydroxypropyl)methacry-lamide] in mice using contrast enhanced MRI. Pharm. Res. 24, 1208–1216.CrossRefPubMedGoogle Scholar
  62. 62.
    Visentin, R., Pasut, G., Veronese, F.M., Mazzi U. (2004) Highly efficient Technetium-99 m labeling procedure based on the conjugation of N-[N-(3-Diphenylphosphinopropionyl)glycyl]cysteine ligand with poly(ethylene glycol). Bioconjug. Chem., 15, 1046–1054.CrossRefPubMedGoogle Scholar
  63. 63.
    Meléndez-Alafort, L., Nadali, A., Pasut, G., Zangoni, E., De Caro, R., Cariolato, L., Giron, M.C., Castagliuolo, I., Veronese, F.M., Mazzi, U. (2009) Detection of sites of infection in mice using 99mTc-labeled PN(2)S-PEG conjugated to UBI and 99mTc-UBI: a comparative biodistribution study. Nucl. Med. Biol. 36, 57–64.CrossRefPubMedGoogle Scholar
  64. 64.
    Vallera, D.A., Sicheneder, A.R., Taras, E.P., Brechbiel, M.W., Vallera, J.A., Panoskaltsis-Mortari, A., Burns, L.J. (2007) Radiotherapy of CD45-expressing Daudi tumours in nude mice with yttri-um-90-labeled, PEGylated anti-CD45 antibody. Cancer Biother. Radiopharm. 22, 488–500.CrossRefPubMedGoogle Scholar
  65. 65.
    Mero, A., Pasut, G., Via, L.D., Fijten, M.W.M., Schubert, U.S., Hoogenboom, R., Veronese, F.M. (2008) Synthesis and characterization of poly(2-ethyl 2-oxazoline) conjugates with proteins and drugs: Suitable alternatives to PEG-conjugates? J. Control. Release, 125, 87–95.CrossRefPubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • Anna Mero
    • 1
    • 2
  • Gianfranco Pasut
    • 1
    • 2
  • Francesco M. Veronese
    • 1
    • 2
  1. 1.Department of Pharmaceutical SciencesUniversity of PaduaPadovaItaly
  2. 2.Department of Pharmaceutical SciencesUniversity of PaduaPaduaItaly

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