The dawning era of polymer therapeutics (original) (raw)

• Duncan, R., Dimitrijevic, S. & Evagorou, E. G. The role of polymer conjugates in the diagnosis and treatment of cancer. S. T. P. Pharma Sciences 6, 237–263 (1996).
  Google Scholar
• Donaruma, L. G. Synthetic biologically active polymers. Progr. Polym. Sci. 4, 1–25 (1974).
  Google Scholar
• Duncan, R. in Handbook of Anticancer Drug Development (eds Budman, D., Calvert, H. & Rowinsky, E.) (Lippincott Williams & Wilkins, Baltimore, in the press). A detailed overview describing the rationale for the design and current clinical status of polymer–anticancer-drug conjugates.
• Harris, J. M. & Chess, R. B. Effect of pegylation on pharmaceuticals. Nature Rev. Drug Discov. 2, 214–221 (2003). An excellent review describing PEG–protein technology and the current clinical status of PEGylated protein pharmaceuticals. An important complementary review to the one presented here.
  CAS Google Scholar
• Veronese, F. M. & Harris, J. M. (eds). Special issue: Peptide and protein PEGylation. Adv. Drug Deliv. Systems 54, 453–609 (2002).
  CAS Google Scholar
• Yokoyama, M. et al. Polymeric micelles as novel drug carrier: Adriamycin-conjugated poly(ethylene glycol)–poly(aspartic acid) block copolymer. J. Control Release 11, 269–278 (1990).
  CAS Google Scholar
• Kabanov, A. V., Felgner, P. L. & Seymour, L. W. Self–assembling Complexes for Gene Delivery. From Laboratory to Clinical Trial (Wiley, Chichester, 1998).
  Google Scholar
• Fuertges, F. & Abuchowski, A. The clinical efficacy of poly(ethylene glycol)-modified proteins. J. Cont. Rel. 11, 139–148 (1990).
  CAS Google Scholar
• Jatzkewitz, H. Peptamin (glycyl-L-leucyl-mescaline) bound to blood plasma expander (polyvinylpyrrolidone) as a new depot form of a biologically active primary amine (mescaline). Z. Naturforsch. 10, 27–31 (1955).
  Google Scholar
• Regelson, W. & Parker, G. The routinization of intraperitoneal (intracavitary) chemotherapy and immunotherapy. Cancer Invest. 4, 29–42 (1986).
  CAS PubMed Google Scholar
• Ringsdorf, H. Structure and properties of pharmacologically active polymers. J. Polymer Sci. Polymer Symp. 51, 135–153 (1975).
  CAS Google Scholar
• Gros, L., Ringsdorf, H. & Schupp, H. Polymeric antitumour agents on a molecular and on a cellular level? Angew. Chem. Int. Edn Engl. 20, 305–325 (1981). The starting point for the development of the modern concepts of polymer–drug conjugates and polymeric micelles.
  Google Scholar
• Davis, F. F. The origin of pegnology. Adv. Drug Deliv. Rev. 54, 457–458 (2002).
  CAS PubMed Google Scholar
• Ferber, D. Gene therapy: Safer and virus-free? Science 294, 1638–1640 (2001).
  CAS PubMed Google Scholar
• Niidome, T. & Huang, L. Gene therapy progress and prospects: Nonviral vectors. Gene Ther. 9, 1647–1652 (2002).
  CAS PubMed Google Scholar
• Gore, M. E. Gene therapy can cause leukaemia: no shock, mild horror but a probe. Gene Ther. 10, 4 (2003). Observations indicating that retroviral gene insertion is linked with leukaemia in two children previously treated with gene therapy for severe combined immunodeficiency syndrome have refuelled interest in the design of effective nonviral vectors for gene therapy.
  CAS Google Scholar
• Brocchini, S. & Duncan, R. in Encyclopaedia of Controlled Drug Delivery (ed. Mathiowitz, E.) 786–816 (Wiley, New York, 1999). A comprehensive review describing the many polymers that have been used to synthesize polymer–drug conjugates.
  Google Scholar
• Rihova, B. Antibody-targeted polymer-bound drugs. Folia Microbiol. 40, 367–384 (1995).
  CAS Google Scholar
• Nori, A. et al. Tat-conjugated synthetic macromolecules facilitate cytoplasmic drug delivery to human ovarian carcinoma cells. Bioconj. Chem. 14, 44–50 (2003).
  CAS Google Scholar
• Satchi, R., Connors, T. A. & Duncan, R. PDEPT: Polymer directed enzyme prodrug therapy. I. HPMA copolymer–cathepsin B and PK1 as a model combination. Brit. J. Cancer 85, 1070–1076 (2001).
  CAS PubMed PubMed Central Google Scholar
• Mammen, M., Choi, S. -K. & Whitesides, G. M. Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors. Angew. Chem. Int. Edn Engl. 37, 2754–2794 (1998).
  Google Scholar
• Stiriba, S. E., Krautz, H. & Frey, H. Hyperbranched molecular nanocapsules: Comparisons of the hyperbranched architecture with the perfect linear analogue. J. Am. Chem. Soc. 124, 9698–9699 (2002).
  CAS PubMed Google Scholar
• Ferruti, P. et al. A novel modification of poly(L-lysine) leading to a soluble cationic polymer with reduced toxicity and with potential as a transfection agent. Macromol. Chem. Phys. 199, 2565–2575 (1998).
  CAS Google Scholar
• Dautzenberg, H. et al. Polycationic graft copolymers as carriers for oligonucleotide delivery. Complexes of oligonucleotides with polycationic graft copolymers. Langmuir 17, 3096–3102 (2001).
  CAS Google Scholar
• Tomalia, D. A. et al. A new class of polymers — starburst-dendritic macromolecules. Polym. J. 17, 117–132 (1985). The start of the dendrimer chemistry revolution.
  CAS Google Scholar
• Frechet, J. M. J. Dendrimers and hyperbranched polymers: two families of three-dimensional macromolecules with similar but clearly distinct properties. J. Mater. Sci. Pure Appl. Chem. 33, 1399–1425 (1996).
  Google Scholar
• Frechet, J. M. J. & Tomalia, D. A. Dendrimers and Other Dendritic Polymers (Wiley, Chichester, 2001).
  Google Scholar
• Malenfant, P. R. L. & Frechet, J. M. J. in Dendrimers and Other Dendritic Polymers (eds Frechet, J. M. J. & Tomalia, D. A.) 171–196 (Wiley, Chichester, 2001).
  Google Scholar
• Pechar, M., Ulbrich, K. & Subr, V. Poly(ethyleneglycol) multiblock copolymer as a carrier of anticancer drug doxorubicin. Bioconj. Chem. 11, 131–139 (2000).
  CAS Google Scholar
• Mirhra, M. K. & Kobayashi, S. Star and Hyperbranched Polymers (Marcel Dekker, Basel, 1999).
  Google Scholar
• Roy, R. Recent developments in the rational design of multivalent glycoconjugates. Top. Curr. Chem. 187, 241–274 (1997).
  CAS Google Scholar
• Chaves, F. et al. Synthesis, isolation and characterization of Plasmodium falciparum antigenic tetrabranched peptide dendrimers obtained by thiazolidine linkages. J. Pept. Res. 58, 307–316 (2001).
  CAS PubMed Google Scholar
• Martin, C. R. & Kohli, P. The emerging field of nanotube biotechnology. Nature Rev. Drug Discov. 2, 29–37 (2003).
  CAS Google Scholar
• Painter, P. C. & Coleman, M. C. Fundamentals of Polymer Science 2nd edn (CRC, Boca Raton, 1997).
  Google Scholar
• Cavagnaro, J. A. Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Nature Rev. Drug Discov. 1, 469–476 (2002).
  CAS Google Scholar
• Seymour, L. W. Synthetic polymers with intrinsic anticancer activity. J. Bioact. Comp. Polymers 6, 178–216 (1991).
  CAS Google Scholar
• Breslow, D. S. Biologically active synthetic polymers. Pure Appl. Chem. 46, 103–113 (1976).
  CAS Google Scholar
• Regelson, W. Advances in intraperitoneal (intracavitary) administration of synthetic polymers for immunotherapy and chemotherapy. J. Bioact. Comp. Polymers 1, 84–106 (1986).
  CAS Google Scholar
• Mistry, C. D. & Gokal, R. Icodextrin in peritoneal dialysis: Early development and clinical use. Perit. Dial. Int. 14 (Suppl. 2), 13–21 (1994).
  Google Scholar
• Jarvan, C. M. et al. Anti-HIV type 1 activity of sulfated derivatives of dextrin against primary viral isolates of HIV type 1 in lymphocytes and monocyte-derived macrophages. AIDS Res. Hum. Retroviruses 13, 875–880 (1997).
  Google Scholar
• Shaunak, S. et al. Reduction of the viral load of HIV-1 after the intraperitoneal administration of dextrin-2-sulphate in patients with AIDS. AIDS 12, 399–409 (1998). Dextrin-2–sulphate was the first sulphated polysaccharide to be administered clinically via the peritoneal route.
  CAS PubMed Google Scholar
• Thornton, M. et al. Anti-Kaposi's sarcoma and angiogenic activities of sulfated dextrins. Antimicrob. Agents Chemother. 43, 2528–2533 (1999).
  CAS PubMed PubMed Central Google Scholar
• Stafford, M. K. et al. A placebo-controlled, double-blind prospective study in healthy female volunteers of dextrin sulphate gel: novel potential intravaginal virucide. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 14, 213–218 (1997).
  CAS PubMed Google Scholar
• Teitlebaum, M. S. D., Arnon, R. & Sela, M. Copaxone in experimental allergic encephalomyelitis and animal model for CMLS. Cell Biol. Life Sci. 53, 24–28 (1997).
  Google Scholar
• Johnson, K. P. et al. Copaxone disease progression. Neurology 45, 1268–1276 (1995).
  CAS PubMed Google Scholar
• Slatopolsky, E. A. et al. RenaGel®, a nonabsorbed calcium- and phosphate-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int. 55, 299–307 (1999).
  CAS PubMed Google Scholar
• Mandeville, W. H. & Goldberg, D. I. The sequestration of bile acids, a non-absorbed method for cholersterol reduction. A review. Curr. Pharm. Des. 3, 15–28 (1997).
  CAS Google Scholar
• Gregoriadis, G. et al. Polysialic acids: potential in drug delivery. FEBS Lett. 315, 271–276 (1993).
  CAS PubMed Google Scholar
• Roy, R. et al. Synthesis and antigenic properties of sialic acid-base dendrimers. ACS Symp. Ser. 560, 104–119 (1994).
  CAS Google Scholar
• Sigal, G. B. et al. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza virus: The strong inhibition reflects enhanced binding through cooperative polyvalent interactions. J. Am. Chem. Soc. 118, 3789–3800 (1996).
  CAS Google Scholar
• Rihova, B. & Riha, I. Immunological problems of polymer-bound drugs. Crit. Rev. Ther. Drug Carrier Syst. 1, 311–374 (1985).
  PubMed Google Scholar
• Rihova, B. Biocompatibility of biomaterials: Haemocompatibility, immunocompatibility and biocompatibility of solid polymeric materials and soluble targetable polymeric carriers. Adv. Drug Deliv. Rev. 21, 157–176 (1996). An excellent review addressing the issues relating to the safety of polymeric materials and water soluble polymers used as drug carriers.
  CAS Google Scholar
• Seymour, L. W. et al. Effect of molecular weight (Mω) of _N_-(2-hydroxypropyl) methacrylamide copolymers on body distributions and rate of excretion after subcutaneous, intraperitoneal and intravenous administration to rats. J. Biomed. Mat. Res. 21, 1341–1358 (1987).
  CAS Google Scholar
• Kobayashi, H. et al. Micro-MR angiography of normal and intratumoural vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: Reference to pharmacokinetic properties of dendrimer-based MR contrast agents. J. Magn. Reson. Imaging 14, 705–713 (2001).
  CAS PubMed Google Scholar
• Robinson, B. V. et al. PVP: A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone (Povidone). (Lewis, Chelsea, 1990).
  Google Scholar
• Seymour, L. W. et al. Influence of molecular weight on passive tumour accumulation of a soluble macromolecular drug carrier. Eur. J. Cancer 31, 766–770 (1995).
  Google Scholar
• Volfova, I. et al. Biocompatibility of biopolymers. J. Bioact. Biocompat. Polymers 7, 175–190 (1992).
  CAS Google Scholar
• Rihova, B. Immunogenicity of _N_-(2-hydroxypropyl) methacrylamide copolymers. Makromol. Chem. 9, 13–24.
• Rihova, B. et al. Biocompatibility of _N_-(2-hydroxypropyl) methacrylamide copolymers containing adriamycin. Immunogenicity, and effect of haematopoietic stem cells in bone marrow in vivo and effect on mouse splenocytes and human peripheral blood lymphocytes in vitro. Biomaterials 10, 335–342 (1989).
  CAS PubMed Google Scholar
• Yeung, T. K. et al. Reduced cardiotoxicity of doxorubicin given in the form of _N_-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat. Cancer Chemother. Pharmacol. 29, 105–111 (1991).
  CAS PubMed Google Scholar
• Duncan, R., Coatsworth, J. K. & Burtles, S. Preclinical toxicology of a novel polymeric antitumour agent: HPMA copolymer–doxorubicin (PK1). Hum. Exp. Toxicol. 17, 93–104 (1998). The first paper describing a good laboratory practice (GLP) preclinical toxicological study of a polymer–drug conjugate.
  CAS PubMed Google Scholar
• Nagle, T. et al. The further evolution of biotech. Nature Rev. Drug Discov. 2, 75–79 (2003).
  CAS Google Scholar
• Brekke, O. H. & Sandlie, I. Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nature Rev. Drug Discov. 2, 52–62 (2003).
  CAS Google Scholar
• Nucci, M. L., Shorr, D. & Abuchowski, A. The therapeutic values of poly(ethylene glycol)-modified proteins. Adv. Drug Deliv. Rev. 6, 133–151 (1991).
  CAS Google Scholar
• Delgado, C., Francis, G. E. & Fisher, D. The uses and properties of PEG-linked proteins. Crit. Rev. Ther. Drug Carrier Syst. 9, 249–304 (1992).
  CAS PubMed Google Scholar
• Monfardini, C. & Veronese, F. M. Stabilisation of substances in the circulation. Bioconj. Chem. 9, 418–450 (1998).
  CAS Google Scholar
• Francis, G. et al. Polyethylene glycol modification: Relevance to improved methodology to tumour targeting. J. Drug Target. 3, 321–340 (1996).
  CAS PubMed Google Scholar
• Roberts, M. J., Bentley, M. D. & Harris, J. M. Chemistry for peptide and protein PEGylation. Adv. Drug Deliv. Rev. 54, 459–476 (2002).
  CAS PubMed Google Scholar
• Goodson, R. J. & Katre, N. V. Site-directed pegylation of recombinant interleukin-2 at its glycosylation site. Biotechnology 8, 343–346 (1990).
  CAS PubMed Google Scholar
• Chapman, A. P. et al. Therapeutic antibody fragments with prolonged in vivo half-lives. Nature Biotechnol. 17, 780–783 (1999).
  CAS Google Scholar
• Sato, H. Enzymatic procedure for site-specific pegylation of proteins. Adv. Drug Deliv. Rev. 54, 487–504 (2002).
  CAS PubMed Google Scholar
• Bailon, P. & Berthold, W. Polyethylene glycol-conjugated pharmaceutical proteins. Pharm. Sci. Technol. Today 1, 352–356 (1998).
  CAS Google Scholar
• Lee, S et al. Drug delivery systems employing 1,6-elimination: Releasable poly(ethylene glycol) conjugates of proteins. Bioconj. Chem. 12, 163–169 (2001).
  CAS Google Scholar
• Levy, Y. et al. Adenosine deaminase deficiency with late onset or recurrent infections: response to treatment with polyethylene glycol modified adenosine deaminase. J. Pediatr. 113, 312–317 (1988).
  CAS PubMed Google Scholar
• Graham, M. L. PEGASPARAGINASE: a review of clinical studies. Adv. Drug Deliv. Rev. (in the press).
• Kinstler, O. et al. Mono-N-terminal poly(ethylene glycol)-protein conjugates. Adv. Drug Deliv. Rev. 54, 477–485 (2002).
  CAS PubMed Google Scholar
• Reddy, K. R., Modi, M. W. & Pedder, S. Use of peginterferon α-2a (40KD) (Pegasys®) for the treatment of hepatitis C. Adv. Drug Deliv. Rev. 54, 571–586 (2002).
  Google Scholar
• Wang, Y. -S. et al. Structural and biological characterisation of pegylated recombinant interferon α-2b and its therapeutic implications. Adv. Drug Deliv. Rev. 54, 547–570 (2002).
  CAS PubMed Google Scholar
• Bukowski, R. et al. Pegylated interferon α-2b treatment for patients with solid tumors: a phase I/II study. J. Clin. Oncol. 20, 3841–3849 (2002).
  CAS PubMed Google Scholar
• De Duve, C. et al. Lysosomotropic agents. Biochem. Pharmacol. 23, 2495–2531 (1974).
  CAS PubMed Google Scholar
• Huang, P. S. & Oliff, A. Drug-targeting strategies in cancer therapy. Curr. Opin. Genet. Dev. 11, 104–110 (2001).
  CAS PubMed Google Scholar
• Duncan, R. & Spreafico, F. Polymer conjugates: Pharmacokinetic considerations for design and development. Clin. Pharmacokinet. 27, 290–306 (1994).
  CAS PubMed Google Scholar
• Matsumura, Y. & Maeda, H. A new concept for macromolecular therapies in cancer chemotherapy: mechanism of tumouritropic accumulation of proteins and the antitumour agent SMANCS. Cancer Res. 6, 6387–6392 (1986).
  Google Scholar
• Seymour, L. W. et al. Tumouritropism and anticancer efficacy of polymer-based doxorubicin prodrugs in the treatment of subcutaneous murine B16F10 melanoma. Brit. J. Cancer 70, 636–641 (1994).
  CAS PubMed PubMed Central Google Scholar
• Gianasi, E. et al. HPMA copolymer platinates as novel antitumor agents: in vitro properties, pharmacokinetics and antitumour activity in vivo. Eur. J. Cancer 35, 994–1002 (1999).
  CAS PubMed Google Scholar
• Rejmanova, P. et al. Stability in plasma and serum of lysosomally degradable oligopeptide sequences in _N_-(2-hydroxypropyl) methacrylamide copolymers. Biomaterials 6, 45–48 (1985).
  CAS PubMed Google Scholar
• Duncan, R. et al. Polymers containing enzymatically degradable bonds. 7. Design of oligopeptide side chains in poly[_N_-(2-hydroxypropyl)methacrylamide] copolymers to promote efficient degradation by lysosomal enzymes. Makromol. Chem. 184, 1997–2008 (1984).
  Google Scholar
• Etrych, T. et al. New HPMA copolymers containing doxorubicin bound via pH-sensitive linkage: synthesis and preliminary in vitro and in vivo biological properties. J. Control Release 73, 89–102 (2001).
  CAS PubMed Google Scholar
• Kopecek, J. & Bazilova, H. Poly[_N_-(hydroxypropyl) methacrylamide]. I. Radical polymerisation and copolymerisation. Eur. Polymer J. 9, 7–14 (1973).
  CAS Google Scholar
• Sprincl, L. et al. New types of synthetic infusion solutions. III. Elimination and retention of poly[_N_-(2-hydroxypropyl) methacrylamide] in a test organism. J. Biomed. Mater. Res. 10, 953–963 (1976).
  CAS PubMed Google Scholar
• Duncan, R. & Kopecek, J. Soluble synthetic polymers as potential drug carriers. Adv. Polymer Sci. 57, 51–101 (1984).
  CAS Google Scholar
• Duncan, R. Drug–polymer conjugates: potential for improved chemotherapy. Anticancer Drugs 3, 175–210 (1992).
  CAS PubMed Google Scholar
• Duncan, R. et al. Preclinical evaluation of polymer-bound doxorubicin. J. Control Release 19, 331–346 (1992). An important paper describing the preclinical and in vivo antitumour studies that paved the way for HPMA copolymer–doxorubicin to enter clinical testing.
  CAS Google Scholar
• Kopecek, J. et al. HPMA copolymer–anticancer drug conjugates: design, activity and mechanism of action. Eur. J. Pharm. Biopharm. 50, 61–81 (2000).
  CAS PubMed Google Scholar
• Vasey, P. et al. Phase I clinical and pharmacokinetic study of PKI (_N_-(2-hydroxypropyl)methacrylamide copolymer doxorubicin): first member of a new class of chemotherapeutic agents — drug–polymer conjugates. Clin. Cancer Res. 5, 83–94 (1999). The first Phase I clinical trial evaluating a synthetic polymer–drug conjugate as an anticancer agent.
  CAS PubMed Google Scholar
• Seymour, L. W. et al. Hepatic drug targeting: Phase I evaluation of polymer-bound doxorubicin. J. Clin. Oncol. 20, 1668–1676 (2002). The first clinical study describing a synthetic biomimetic polymer conjugate. HPMA copolymer–doxorubicin containing additional galactose residues was designed to target the hepatocyte asialoglycoprotein receptor.
  CAS PubMed Google Scholar
• Thomson, A. H. et al. Population pharmacokinetics in phase I drug development: a phase I study of PK1 in patients with solid tumours. Brit. J. Cancer 81, 99–107 (1999).
  CAS PubMed PubMed Central Google Scholar
• Duncan, R. et al. Fate of _N_-(2-hydroxypropyl) methacrylamide copolymers with pendant galactosamine residues after intravenous administration to rats. Biochim. Biophys. Acta 880, 62–71 (1986).
  CAS PubMed Google Scholar
• Ashwell, G. & Harford, J. Carbohydrate recognition systems of the liver. Ann. Rev. Biochem. 51, 531–554 (1982).
  CAS PubMed Google Scholar
• Julyan, P. J. et al. Preliminary clinical study of the distribution of HPMA copolymer–doxorubicin bearing galactosamine. J. Control Release 57, 281–290 (1999).
  CAS PubMed Google Scholar
• Meerum Terwogt, J. M. et al. Phase I clinical and pharmacokinetic study of PNU166945, a novel water soluble polymer-conjugated prodrug of paclitaxel. Anticancer Drugs 12, 315–323 (2001).
  CAS PubMed Google Scholar
• Schoemaker, N. E. et al. A phase I and pharmacokinetic study of MAG-CPT, a water soluble polymer conjugate of camptothecin. Brit. J. Cancer 87, 608–614 (2002).
  CAS PubMed PubMed Central Google Scholar
• Li, C. et al. Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)–paclitaxel conjugate. Cancer Res. 58, 2404–2409 (1998). An important study describing preclinical properties of PGA–paclitaxel.
  CAS PubMed Google Scholar
• Sludden, A. V. et al. Phase I and pharmacological study of CT-2103, a poly(L-glutamic acid)–paclitaxel conjugate. Proc. Am. Assoc. Cancer Res. 42, 2883 (2001).
  Google Scholar
• Sabbatini, P. et al. A phase I/II study of PG–paclitaxel (CT-2103) in patients (pts) with recurrent ovarian, fallopian tube, or peritoneal cancer. Proc. Am. Soc. Clin. Oncol. 871 (2002).
• Kudelka, A. P. et al. Preliminary report of a phase I study of escalating dose PG–paclitaxel (CT-2103) and fixed dose cisplatin in patients with solid tumors Proc. Am. Soc. Clin. Oncol. 2146 (2002).
• Schulz, J. et al. Phase II study of CT-2103 in patients with colorectal cancer having recurrent disease after treatment with a 5-fluorouracil-containing regimen. Proc. Am. Soc. Clin. Oncol. 2330 (2002).
• Shaffer, S. A. et al. Metabolism of poly-L-glutamic acid (PG)–paclitaxel (CT-2103); proteolysis by lysosomal cathepsin B and identification of intermediate metabolites. Proc. Am. Assoc. Cancer Res. 43, 2067 (2002).
  Google Scholar
• Denis, L. et al. A Phase I study of PEG–camptothecin (PEG–CPT) in patients with advanced solid tumours: A novel formulation for an insoluble but active agent. Proc. Am. Soc. Clin. Oncol. 19, 700 (2000).
  Google Scholar
• Greenwald, R. B. et al. Effective drug delivery by PEGylated drug conjugates. Adv. Drug Deliv. Rev. 55, 217–250 (2003).
  CAS PubMed Google Scholar
• Rice, J. R., Stewart, D. R. & Nowotnik, D. P. Enhanced antitumour activity of a new polymer linked DACH–platinum complex. Proc. Am. Assoc. Cancer Res. 43, 307 (2002).
  Google Scholar
• Gianasi, E. et al. HPMA copolymers platinates containing dicarboxylato ligands. Preparation, characterisation and in vitro and in vivo evaluation. J. Drug Targeting 10, 549–556 (2002).
  CAS Google Scholar
• Ochi, Y. et al. DE-310, a novel macromolecular carrier for the camptothecin analogue DX-8951f[II]: Its antitumour activities in several model systems of human and murine tumours. Proc. Am. Assoc. Cancer Res. 42, 748 (2001).
  Google Scholar
• De Vries, P. et al. Optimisation of CT2106: a water soluble poly-L-glutamic acid (PG)–camptothecin conjugate with enhanced in vivo antitumor efficacy. Proc. AACR-NCI-EORTC Int. Conf. 100 (2001).
• Batrakova, E. V. et al. Anthracycline antibiotics non-covalently incorporated into block copolymer micelles: in vivo evaluation of anticancer activity. Br. J. Cancer 74, 1545–1552 (1996).
  CAS PubMed PubMed Central Google Scholar
• Alakhov, V. et al. Block copolymer-based formulations of doxorubicin. From cell screen to clinical trials. Colloids Surf. B: Biointerfaces 16, 113–134 (1999). The first micelle-based formulation of doxorubicin, and its transfer to the clinic.
  CAS Google Scholar
• Kataoka, K. et al. Block copolymer micelles as vehicles for drug delivery. J. Control Release 24, 119–132 (1993).
  CAS Google Scholar
• Nakanishi, T. et al. Development of the polymer micelle carrier system for doxorubicin. J. Control Release 74, 295–302 (2001). A description of the preclinical development of the first micelle-based doxorubicin formulation containing covalently bound drug.
  CAS PubMed Google Scholar
• Sat, Y. N. et al. Comparison of vascular permeability and enzymatic activation of the polymeric prodrug HPMA copolymer–doxorubicin (PK1) in human tumour xenografts. Proc. Am. Assoc. Cancer Res. 90, 41 (1999).
  Google Scholar
• Jain, R. K. Delivery of molecular and cellular medicine to solid tumours. Adv. Drug Deliv. Rev. 46, 149–168 (2001).
  CAS PubMed Google Scholar
• Wu, J., Akaike, T. & Maeda, H. Modulation of enhanced vascular permeability in tumours by a bradykinin antagonist, a cyclooxygenase inhibitor. Cancer Res. 58, 159–165 (1998).
  CAS PubMed Google Scholar
• Li, C. et al. Tumour irradiation enhances the tumour-specific distribution of poly(L-glutamic acid)–conjugated paclitaxel and its antitumour efficacy. Clin. Cancer Res. 6, 2829–2834 (2000).
  CAS PubMed Google Scholar
• Boussif, O. et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: Polyethylenimine. Proc. Natl Acad. Sci. USA 92, 7297–7301 (1995).
  CAS PubMed PubMed Central Google Scholar
• Remy, J. -S. et al. Gene transfer with lipospermines and polyethylenimines. Adv. Drug Deliv. Rev. 30, 85–95 (1998).
  CAS PubMed Google Scholar
• Merdan, T. et al. Intracellular processing of poly(ethyleneimine)/ribozyme complexes can be observed in living cells by using confocal laser scanning microscopy and inhibitor experiments. Pharm. Res. 19, 140–146 (2002).
  CAS PubMed Google Scholar
• Brunner, S. et al. Overcoming the nuclear barrier: cell cycle independent nonviral gene transfer with linear polyethylenimine or electroporation. Mol. Ther. 5, 80–86 (2002).
  CAS PubMed Google Scholar
• Wightman, L. et al. Different behavior of branched and linear polyethylenimine for gene delivery in vitro and in vivo. J. Gene Med. 3, 362–372 (2001).
  CAS PubMed Google Scholar
• Kircheis, R. et al. Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application. Gene Ther. 8, 28–40 (2001).
  CAS PubMed Google Scholar
• Lisziewicz, J. et al. Induction of potent human immunodeficiency virus type 1-specific T cell-restricted immunity by genetically modified dendritic cells. J. Virol. 75, 7621–7628 (2001).
  CAS PubMed PubMed Central Google Scholar
• Vernejoul, F. Antitumor effect of in vivo somatostatin receptor sst2 gene transfer in primary and metastatic pancreatic cancer models. Cancer Res. 62, 6124–6131 (2002).
  CAS PubMed Google Scholar
• Ferruti, P., Marchisio, M. A. & Duncan, R. Poly(amido-amine)s: Biomedical applications Macromol. Rapid Comm. 23, 332–355 (2002).
  CAS Google Scholar
• Stayton, P. S. et al. Molecular engineering of proteins and polymers for targeting and intracellular delivery of therapeutics. J. Control Release 65, 203–220 (2000).
  CAS PubMed Google Scholar
• Putnam, D. et al. Polymer-based gene delivery with low cytotoxicity by a unique balance of side chain termini. Proc. Natl Acad Sci. USA 98, 1200–1205 (2001).
  CAS PubMed PubMed Central Google Scholar
• Satchi-Fainaro, R. et al. PDEPT: Polymer directed enzyme prodrug therapy. II. HPMA copolymer-β-lactamase and HPMA-C-Dox as a model combination. Bioconj. Chem. (in the press).
• Duncan, R. et al. Polymer–drug conjugates, PDEPT and PELT: Basic principles for design and transfer from the laboratory to the clinic. J. Control Release 74, 135–146 (2001).
  CAS PubMed Google Scholar
• Gopin, A. et al. A chemical adaptor system designed to link a tumor-targeting device with a prodrug and an enzymatic trigger. Angew. Chem. Int. Edn Engl. 42, 327–332 (2003).
  CAS Google Scholar
• Kerbel, R. & Folkman, J. Clinical translation of angiogenic inhibitors. Nature Rev. Cancer 2, 727–739 (2002).
  CAS Google Scholar
• Satchi-Fainaro, R. et al. Polymer therapeutics of angiogenesis inhibitors: HPMA copolymer–TNP-470 conjugate. Proc. Intl Symp. Controlled Rel. Bioact. Mater. 29, 209–210 (2002). An excellent paper describing in vitro and in vivo activity of the first polymer anti-angiogenic conjugate.
  Google Scholar
• Tomlinson, R. et al. Pendent chain functionalised polyacetals that display pH-dependent degradation: A platform for the development of novel polymer therapeutics. Macromolecules 35, 473–480 (2002).
  CAS Google Scholar
• Gillies, E. R. & Frechet, J. M. J. Designing macromolecules for therapeutic applications: Polyester dendrimer–poly(ethylene oxide) 'bow-tie' hybrids with tunable molecular weight and architecture. J. Am. Chem. Soc. 124, 14137–14146 (2002).
  CAS PubMed Google Scholar
• Cloninger, M. J. Biological applications of dendrimers. Curr. Opin. Chem. Biol. 6, 742–748 (2002).
  CAS PubMed Google Scholar
• Wiwattanapatapee, R. et al. Anionic PAMAM dendrimers rapidly cross adult rat intestine in vitro: A potential oral delivery system. Pharm. Res. 17, 991–998 (2000).
  CAS PubMed Google Scholar
• Lendlein, A. & Langer, R. Biodegradable, elastic, shape-memory polymers for potential biomedical applications. Science 296, 1673–1676 (2002).
  PubMed Google Scholar
• Chanda, S. K. & Caldwell, J. S. Fulfilling the promise: drug discovery in the post-genomic era. Drug Discov. Today 8, 168–174 (2003).
  CAS PubMed Google Scholar
• Atkins, J. H. & Gershell, L. J. Selective anticancer drugs. Nature Rev. Cancer 1, 645–646 (2002).
  Google Scholar
• The Journal of Gene Medicine, www.wiley.co.uk.genmed (2002).
• Jain, R. K. The next frontier of molecular medicine: Delivery of therapeutics. Nature Med. 4, 655–657 (1998).
  CAS PubMed Google Scholar
• Allen, T. M. Ligand-targeted therapeutics in anticancer therapy. Nature Rev. Drug Discov. 2, 750–763 (2002). An excellent review describing ligands and technologies that have been explored for tumour targeting. Includes information on antibodies, immunoliposomes, immunotoxins and immuno–polymer conjugates.
  CAS Google Scholar
• Langer, R. Drug delivery and targeting. Nature 392, 5–10 (1998).
  CAS PubMed Google Scholar
• Iwai, K., Maeda, H. & Konno, T. Use of oily contrast medium for selective drug targeting to tumour: Enhanced therapeutic effect and X-ray image. Cancer Res. 44, 2114–2121 (1984).
  Google Scholar
• Konno, T. & Maeda, H. in Neoplsma of the Liver (eds Okada, K. & Ishak, K. G.) 343–352 (Springer, New York, 1987).
  Google Scholar
• Maeda, H. & Konno, T. in Neocarzinostatin: The Past, Present, and Future of an Anticancer Drug (eds Maeda, H., Edo, K. & Ishida, N.) 227–267 (Springer, Berlin, 1997).
  Google Scholar
• Jain, R. K. Delivery of molecular and cellular medicines to solid tumours. Adv. Drug Deliv. Rev. 26, 71–90 (1997).
  CAS PubMed Google Scholar
• Mukherjee, A. et al. How to optimise pegvisomant treatment of acromegaly safely? Endocrine Abstracts 4, OC8 (2002).
  Google Scholar