The dawning era of polymer therapeutics

Nature Reviews Drug Discovery

Volumn 2, Issue 5, 2003, Pages 347-360

  Duncan, Ruth ^a  

^a CARDIFF UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

1 VINYL 2 PYRROLIDINONE; ADENOSINE DEAMINASE; ANTINEOPLASTIC AGENT; AP 5280; ASPARAGINASE; ASPARAGINASE MACROGOL; ASPARTIC ACID; CAMPTOTHECIN; CD870; CT 2106; DEXTRIN 2 SULFATE; DNA; DOXORUBICIN; FCE 28068; FCE 28069; GALACTOSAMINE; GLATIRAMER; GLYCYLLEUCINE; MACROGOL; MAG CPT; MESCALINE; NANOPARTICLE; NK 911; PACLITAXEL; PACLITAXEL POLIGLUMEX; PEG FILGRASTIM; PEGADEMASE; PEGINTERFERON ALPHA2A; PEGINTERFERON ALPHA2B; PEGVISOMANT; PLATINUM DERIVATIVE; PNU 166148; PNU 166945; POLYANION; POLYELECTROLYTE; POLYMER; PROTEIN; PROTHECAN; PYRAN COPOLYMER; RECOMBINANT GRANULOCYTE COLONY STIMULATING FACTOR; STIMALMER; STYRENE MALEIC ANHYDRIDE COPOLYMER; TUMOR NECROSIS FACTOR ANTIBODY; UNCLASSIFIED DRUG; UNINDEXED DRUG; ZINOSTATIN;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ACROMEGALY; ACUTE LYMPHOBLASTIC LEUKEMIA; BIOMEDICINE; BIOTECHNOLOGY; BLADDER DISEASE; CANCER; CHEMISTRY; CLINICAL TRIAL; COMBINED IMMUNODEFICIENCY; COMPLEX FORMATION; CONJUGATE; COVALENT BOND; DRUG BLOOD LEVEL; DRUG DELIVERY SYSTEM; DRUG DESIGN; DRUG FORMULATION; DRUG HYPERSENSITIVITY; DRUG RESEARCH; GENE DELIVERY SYSTEM; GENOMICS; HEPATITIS C; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; LIVER CELL CARCINOMA; MACROMOLECULE; MICELLE; MUCOSA INFLAMMATION; MULTIPLE SCLEROSIS; NANOTECHNOLOGY; NEUROTOXICITY; NEUTROPENIA; PRIORITY JOURNAL; REVIEW; RHEUMATOID ARTHRITIS; TREATMENT OUTCOME;

ANTINEOPLASTIC AGENTS; DRUG DELIVERY SYSTEMS; DRUG DESIGN; MICELLES; POLYMERS;

EID: 0038387390     PISSN: 14741776     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrd1088     Document Type: Review

References (154)

1. 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).
2. Donaruma, L. G. Synthetic biologically active polymers. Progr. Polym. Sci. 4, 1-25 (1974).
3. Duncan, R. in Handbook of Anticancer Drug Development (eds Budman, D., Calvert, H. & Rowinsky, E.) (Lippincott Williams & Wilkins, Baltimore, in the press).
4. Harris, J. M. & Chess, R. B. Effect of pegylation on pharmaceuticals. Nature Rev. Drug Discov. 2, 214-221 (2003).
5. Veronese, F. M. & Harris, J. M. (eds). Special issue: Peptide and protein PEGylation. Adv. Drug Deliv. Systems 54, 453-609(2002).
6. 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).
7. Kabanov, A. V, Felgner, P. L. & Seymour, L. W. Self-assembling Complexes for Gene Delivery. From Laboratory to Clinical Trial (Wiley, Chichester, 1998).
8. Fuertges, F. & Abuchowski, A. The clinical efficacy of poly(ethylene glycol)-modified proteins. J. Cont. Rel. 11, 139-148 (1990).
9. 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).
10. Regelson, W. & Parker, G. The routinization of intraperitoneal (intracavitary) chemotherapy and immunotherapy. Cancer Invest. 4, 29-42 (1986).
11. Ringsdorf, H. Structure and properties of pharmacologically active polymers. J. Polymer Sci. Polymer Symp. 51, 135-153 (1975).
12. 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).
13. Davis, F. F. The origin of pegnology. Adv. Drug Deliv. Rev. 54, 457-458 (2002).
14. Ferber, D. Gene therapy: Safer and virus-free? Science 294, 1638-1640 (2001).
15. Niidome, T. & Huang, L. Gene therapy progress and prospects: Nonviral vectors. Gene Ther. 9, 1647-1652 (2002).
16. Gore, M. E. Gene therapy can cause leukaemia: no shock, mild horror but a probe. Gene Ther. 10, 4 (2003).
17. Brocchini, S. & Duncan, R. in Encyclopaedia of Controlled Drug Delivery (ed. Mathiowitz, E.) 786-816 (Wiley, New York, 1999).
18. Rihova, B. Antibody-targeted polymer-bound drugs. Folia Microbiol. 40, 367-384 (1995).
19. Nori, A. et al. Tat-conjugated synthetic macromolecules facilitate cytoplasmic drug delivery to human ovarian carcinoma cells. Bioconj. Chem. 14, 44-50 (2003).
20. 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).
21. 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).
22. 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).
23. 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).
24. Dautzenberg, H. et al. Polycationic graft copolymers as carriers for oligonucleotide delivery, Complexes of oligonucleotides with polycationic graft copolymers. Langmuir 17, 3096-3102 (2001).
25. Tomalia, D. A. et al. A new class of polymers - starburst-dendritic macromolecules. Polym. J. 17, 117-132 (1985).
26. 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).
27. Frechet, J. M. J. & Tomalia, D. A. Dendrimers and Other Dendritic Polymers (Wiley, Chichester, 2001).
28. 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).
29. Pechar, M., Ulbrich, K. & Subr, V. Poly(ethyleneglycol) multiblock copolymer as a carrier of anticancer drug doxorubicin. Bioconj. Chem, 11, 131-139 (2000).
30. Mirhra, M. K. & Kobayashi, S. Star and Hyperbranched Polymers (Marcel Dekker, Basel, 1999).
31. Roy, R. Recent developments in the rational design of multivalent glycoconjugates. Top. Curr. Chem. 187, 241-274 (1997).
32. 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).
33. Martin, C. R. & Kohli, P. The emerging field of nanotube biotechnology. Nature Rev. Drug Discov 2, 29-37 (2003).
34. Painter, P. C. & Coleman, M. C. Fundamentals of Polymer Science 2nd edn (CRC, Boca Raton, 1997).
35. Cavagnaro, J. A. Preclinical safety evaluation of biotechnology-derived pharmaceuticals. Nature Rev. Drug Discov. 1, 469-476 (2002).
36. Seymour, L. W. Synthetic polymers with intrinsic anticancer activity. J. Bioact. Comp. Polymers 6, 178-216 (1991).
37. Breslow, D. S. Biologically active synthetic polymers. Pure Appl. Chem, 46, 103-113 (1976).
38. Regelson, W. Advances in intraperitoneal (intracavitary) administration of synthetic polymers for immunotherapy and chemotherapy. J. Bioact. Comp. Polymers 1, 84-106 (1986).
39. Mistry, C. D. & Gokal, R. Icodextrin in peritoneal dialysis: Early development and clinical use. Perit. Dial. Int. 14 (Suppl. 2), 13-21 (1994).
40. 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).
41. 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).
42. Thornton, M. at al. Anti-Kaposi's sarcoma and angiogenic activities of sulfated dextrins. Antimicrob. Agents Chemother. 43, 2528-2533 (1999).
43. 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).
44. 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).
45. Johnson, K. P. et al. Copaxone disease progression. Neurology 45, 1268-1276 (1995).
46. 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).
47. 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).
48. Gregoriadis, G. et al. Polysialic acids: potential in drug delivery, FEBS Lett. 315, 271-276 (1993).
49. Roy, R. et al. Synthesis and antigenic properties of sialic acid-base dendrimers. ACS Symp. Ser. 560, 104-119 (1994).
50. 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).
51. Rihova, B. & Riha, I. Immunological problems of polymer-bound drugs. Crit. Rev. Ther. Drug Carrier Syst. 1, 311-374 (1985).
52. 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).
53. 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).
54. Kobayashi, H. at 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).
55. Robinson, B. V. et al. PVP: A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone (Povidone). (Lewis, Chelsea, 1990).
56. 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).
57. Volfova, I. et al. Biocompatibility of biopolymers. J. Bioact. Biocompat. Polymers 7, 175-190 (1992).
58. Rihove, B. Immunogenicity of N-(2-hydroxypropyl) methacrylamide copolymers. Makromol. Chem. 9, 13-24.
59. 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).
60. 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).
61. 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).
62. Nagle, T. et al. The further evolution of biotech. Nature Rev. Drug Discov. 2, 75-79 (2003).
63. 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).
64. Nucci, M. L., Shorr, D. & Abuchowski, A. The therapeutic values of poly(ethylene glycol)-modified proteins. Adv. Drug Deliv. Rev. 6, 133-151 (1991).
65. 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).
66. Monfardini, C. & Veronese, F. M. Stabilisation of substances in the circulation. Bioconj. Chem. 9, 418-450 (1998).
67. Francis, G. et al. Polyethylene glycol modification: Relevance to improved methodology to tumour targeting. J. Drug Target. 3, 321-340 (1996).
68. Roberts, M. J., Bentley, M. D. & Harris, J. M. Chemistry for peptide and protein PEGylation. Adv. Drug Deliv. Rev. 54, 459-476 (2002).
69. Goodson, R. J. & Katre, N. V. Site-directed pegylation of recombinant interleukin-2 at its glycosylation site. Biotechnology 8, 343-346 (1990).
70. Chapman, A. P. et al. Therapeutic antibody fragments with prolonged in vivo half-lives. Nature Biotechnol. 17, 780-783 (1999).
71. Sato, H. Enzymatic procedure for site-specific pegylation of proteins. Adv. Drug Deliv. Rev. 54, 487-504 (2002).
72. Bailon, P. & Berthold, W. Polyethylene glycol-conjugated pharmaceutical proteins. Pharm. Sci. Technol. Today 1, 352-356 (1998).
73. Lee, S et al. Drug delivery systems employing 1,6-elimination: Releasable poly(ethylene glycol) conjugates of proteins. Bioconj. Chem. 12, 163-169 (2001).
74. 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).
75. Graham, M. L. PEGASPARAGINASE: a review of clinical studies. Adv. Drug Deliv. Rev. (in the press).
76. Kinstler, O. et al. Mono-N-terminal poly(ethylene glycol)-protein conjugates. Adv. Drug Deliv. Rev. 54, 477-485 (2002).
77. 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).
78. 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).
79. 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).
80. De Duve, C. et al. Lysosomotropic agents. Biochem. Pharmacol. 23, 2495-2531 (1974).
81. Huang, P. S. & Oliff, A. Drug-targeting strategies in cancer therapy. Curr. Opin. Genet. Dev. 11, 104-110 (2001).
82. Duncan, R. & Spreafico, F. Polymer conjugates: Pharmacokinetic considerations for design and development. Clin. Pharmacokinet. 27, 290-306 (1994).
83. 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).
84. 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).
85. 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).
86. 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).
87. 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).
88. 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).
89. Kopecek, J. & Bazilova, H. Poly[N-(hydroxypropyl) methacrylamide]. I. Radical polymerisation and copolymerisation. Eur. Polymer J. 9, 7-14 (1973).
90. Sprincl, L. et al. New types of synthetic infusion solutions. III. Elimination and retention of poly(2-hydroxypropyl) methacrylamide] in a test organism. J. Biomed. Mater. Res. 10, 953-963 (1976).
91. Duncan, R. & Kopecek, J. Soluble synthetic polymers as potential drug carriers. Adv. Polymer Sci. 57, 51 -101 (1984).
92. Duncan, R. Drug-polymer conjugates: potential for improved chemotherapy Anticancer Drugs 3, 175-210 (1992).
93. Duncan, R. et al. Preclinical evaluation of polymer-bound doxorubicin. J. Control Release 19, 331-346 (1992).
94. Kopecek, J. et al. HPMA copolymer-anticancer drug conjugates: design, activity and mechanism of action. Eur. J. Pharm. Biopharm. 50, 61-81 (2000).
95. 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).
96. Seymour, L. W. et al. Hepatic drug targeting: Phase I evaluation of polymer bound doxorubicin. J. Clin. Oncol. 20, 1668-1676 (2002).
97. 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).
98. 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).
99. Ashwell, G. & Harford, J. Carbohydrate recognition systems of the liver. Ann. Rev. Biochem. 51, 531-554 (1982).
100. Julyan, P. J. et al. Preliminary clinical study of the distribution of HPMA copolymer-doxorubicin bearing galactosamine. J. Control Release 57, 281-290 (1999).
101. 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).
102. 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).
103. L-glutamic acid)-paclitaxel conjugate. Cancer Res. 58, 2404-2409 (1998).
104. L-glutamic acid)-paclitaxel conjugate. Proc. Am. Assoc. Cancer Res. 42, 2883 (2001).
105. Sabbatini, P. et al. A phase I/II study of PC-paclitaxel (CT-2103) in patients (pts) with recurrent ovarian, fallopian tube, or peritoneal cancer. Proc. Am. Soc. Clin. Oncol. 871 (2002).
106. 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).
107. 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).
108. 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).
109. 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).
110. Greenwald, R. B. et al. Effective drug delivery by PEGylated drug conjugates. Adv. Drug Deliv. Rev. 55, 217-250 (2003).
111. 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).
112. 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).
113. Ochi, Y. et al. DE-310, a novel macromolecular carrier for the camptothecin analogue DX-8951 f[II]: Its antitumour activities in several model systems of human and murine tumours. Proc. Am. Assoc. Cancer Res. 42, 748 (2001).
114. L-glutamic acid (PG)-camptothecin conjugate with enhanced in vivo antitumor efficacy Proc. AACR-NCI-EORTC Int. Conf. 100 (2001).
115. Batrakova, E. V. et al. Anthracycline antibiotics noncovalently incorporated into block copolymer micelles: in vivo evaluation of anticancer activity. Br. J. Cancer 74, 1545-1552 (1996).
116. Alakhov, V. et al. Block copolymer-based formulations of doxorubicin. From cell screen to clinical trials. Colloids Surf. B: Biointerfaces 16, 113-134 (1999).
117. Kataoka, K. et al. Block copolymer micelles as vehicles for drug delivery. J. Control Release 24, 119-132 (1993).
118. Nakanishi, T. et al. Development of the polymer micelle carrier system for doxorubicin. J. Control Release 74, 295-302 (2001).
119. 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).
120. Jain, R. K. Delivery of molecular and cellular medicine to solid tumours. Adv. Drug Deliv. Rev. 46, 149-168 (2001).
121. 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).
122. L-glutamic acid)-conjugated paclitaxel and its antitumour efficacy. Clin. Cancer Res. 6, 2829-2834 (2000).
123. 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).
124. Remy, J.-S. et al. Gene transfer with lipospermines and polyethylenimines. Adv. Drug Deliv. Rev. 30, 85-95 (1998).
125. 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).
126. 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).
127. 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).
128. Kircheis, R. et al. Polyethylenimine/DNA complexes shielded by transferrin target gene expression to tumors after systemic application. Gene Ther. 8, 28-40 (2001).
129. 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).
130. 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).
131. Ferruti, P., Marchisio, M. A. & Duncan, R. Poly(amido-amine)s: Biomedical applications Macromol. Rapid Comm. 23, 332-355 (2002).
132. 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).
133. 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).
134. 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),
135. 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).
136. 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).
137. Kerbel, R. & Folkman, J. Clinical translation of angiogenic inhibitors. Nature Rev. Cancer 2, 727-739 (2002).
138. 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).
139. 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).
140. 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).
141. Cloninger, M. J. Biological applications of dendrimers. Curr. Opin. Chem. Biol. 6, 742-748 (2002).
142. 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).
143. Lendlein, A. & Langer, R. Biodegradable, elastic, shapememory polymers for potential biomedical applications. Science 296, 1673-1676 (2002).
144. Chanda, S. K. & Caldwell, J. S. Fulfilling the promise: drug discovery in the post-genomic, era, Drug Discov. Today 8, 168-174 (2003).
145. Atkins, J. H. & Gershell, L. J. Selective anticancer drugs. Nature Rev. Cancer 1, 645-646 (2002).
146. The Journal of Gene Medicine, www.wiley.co.uk.genmed (2002).
147. Jain, R. K. The next frontier of molecular medicine: Delivery of therapeutics. Nature Med. 4, 655-657 (1998).
148. Allen, T. M. Ligand-targeted therapeutics in anticancer therapy. Nature Rev. Drug Discov. 2, 750-763 (2002).
149. Langer, R. Drug delivery and targeting. Nature 392, 5-10 (1998).
150. 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).
151. Konno, T & Maeda, H. in Neoplsma of the Liver (eds Okada, K. & Ishak, K. G.) 343-352 (Springer, New York, 1987).
152. 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).
153. Jain, R. K. Delivery of molecular and cellular medicines to solid tumours. Adv. Drug Deliv. Rev. 26, 71-90 (1997).
154. Mukherjee, A. et al. How to optimise pegvisomant treatment of acromegaly safely? Endocrine Abstracts 4, OC8 (2002).