METHACRYLAMIDE COPOLYMER

A phase I clinical and pharmacokinetic study of PKl comprising doxorubicin covalently bound to N-(2-hydroxypropyl)-methacrylamide copolymer by a peptidyl linker, was carried out in 36 patients with refractory or resistant cancers [94], PKl demonstrated anti-tumour activity, and that polymer-drug conjugation decreased doxorubicin dose-limiting toxicities. Phase II studies are in progress. 

Seymour, L. W., R. Duncan, J. Strohalm, and I. Kopecek. 1987. Effect of molecular weight (Mw) of N-(2-hydroxypropyl)methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration toJraSSomed. Mater. Res. 21 1341-1358. 

Duncan, R., L C. Seymour, L. Scarlett, J. B. Lloyd, P. Rejmanova, and J. Kopecek. 1986. Fate of N-(2-hydroxypropyl)methacrylamide copolymers with pendent galactosamine residues after intravenous administration to ratfiiochim. Biophys. Act880 62-71. 

Duncan, R., P. Kopeckova-Rejmanova, J. Strohalm, I. Hume, H. C. Cable, J. Pohl, J. B. Lloyd, and J. Kopecek. 1987. Anticancer agents coupled1e(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates/itro. Br. J. Cancei55 165-174. 

David, A., et al. 2002. The role of galactose, lactose, and galactose valency in the biorecognition of lV-(2-hydroxypropyl)methacrylamide copolymers by human adenocarcinoma cells. Pharm Res 19 1114. 

Vasey, P. A., Kaye, S. B., Morrison, R., et al. Phase I clinical and pharmacokinetic study of PK1 [lV-(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. 5(l) 83-94. 1999. 

Rihova, B., Ulbrich, K., Kopecek, J., andMancal, P. Immunogenicity of Af-(2-hydrox-ypropyl)-methacrylamide copolymers Potential hapten or drug carriers. Folia Microbiol. (Praha) 28 217-227, 1983. 

Rihova, B., Bilej, M., Vetvicka, V., et al. Biocompatibility of IV-(2-hydroxypropyl) methacrylamide copolymers containing adriamycin Immunogenicity, and effect on haematopoietic stem cells in bone marrow in vivo and mouse splenocytes and human peripheral blood lymphocytes in vitro. Biomaterials 10 335-342, 1989. 

J. Kopecek, P. Kopecekova, AM 2-hydroxy propyl (methacrylamide copolymers for colon-specific drug delivery, Chapter 7 (D.R. Friend, ed.), Oral Colon-specific Drug Delivery, CRC Press, Boca Raton, 1992, pp. 189-211. 

Tibben, M.M., Rademaker-Lakhai, J.M., Rice, J.R., Stewart, D.R., Schellens, J.H.M., Beijnen, J.H. Determination of total platinum in plasma and plasma ultrafiltrate, from subjects dosed with the platinum-containing N-(2-hydroxypropyl)methacrylamide copolymer AP5280, by use of graphite-furnace Zeeman atomic-absorption spectrometry. Anal. Bioanal. Chem. 373, 233-236 (2002)... 

Vasey, P. Kaye, S.B. Morrison, R. Twelves, C. Wilson, P. Duncan, R. Thomson, A.H. Murray, L.S. Hilditch, T.E. Murray, T. Burtles, S. Fraier, D. Frigerio, E. Cassidy, J. Phase I clinical and pharmacokinetics study of PKl (iV-(2-hydroxy propy l)methacrylamide copolymer doxorubicin) first member of a new class of chemotherapeutic agents - drug-polymer conjugates. Chnical Cancer Research 1999, 5, 83-94. 

Duncan R, Cable HC, Rypacek F, et al. Targeting of soluble crosslinked N-(2-hydroxypropyl) methacrylamide copolymers in vivo—a potential drug delivery system. Biochem Soc Trans 1984 12 1064-1065. 

Duncan R, Cable HC, Rejmanove P, et al. Tyrosinamide residues enhance pinocytic capture of N-(2-hydroxypropyl)methacrylamide copolymers. Biochim Biophys Acta 1984 799 1-8. 

Mitra A, Nan A, Ghandehari H, et al. Technetium-99m-labeled N-(2-hydroxypropyl) methacrylamide copolymers synthesis, characterization, and in vivo biodistribution. Pharm Res 2004 21 1153-1159. 

Bridges JF, Woodley JF, Duncan R, et al. Soluble N-(2-hydroxypropyl) methacrylamide copolymers as a potential oral, controlled-release, drag delivery system. I. Bioadhesion to the rat intestine in vitro. Int J Pharm 1988 44 213-223. 

Zamai, M., vandeVen, M., Farao, M., Gratton, E., Ghiglieri, A., Castelli, M. G., Fontana, E., d Argy, R., Fiorino, A., Pesenti, E., Suarato, A., Caiolfa, V. R. Camptothecin poly[7V-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-1 tumor therapy intratumor release and antitumor efficacy. Mol. Cancer Then 2003, 2, 29—40. 

Shiah, J.-G., Sun, Y., Peterson, C.M., Straight, R.C., and Kopecek, J. (2000) Antitumor activity of A-(2-hydroxypropyl)methacrylamide copolymer-mesochlorin e6 and adriamycin conjugates in combination treatments, Clin. Cancer Res., 6, 1008-1015. 

The first polymer-drug conjugate to be tested in humans for anticancer therapy is doxorubicin coupled with iV-(2-hydroxypropyl)methacrylamide copolymer via a linker that is degraded in lysosomes, thereby releasing the drug [29]. In contrast to the free drug doxorubicin, which has a distribution half-life of 0.08 h and an elimination half-Ufe of 30 h (see Table 8.6), the doxorubicin conjugate has a distribution half-life of 1.8 h and an elimination half-life of 90 h. 

Duncan, R., et al., Macromolecular prodrugs for use in targeted cancer chemotherapy melphalan covalently coupled to Y-(2-hydroxypropyl) methacrylamide copolymers. Journal of Controlled Release, 1991, 16, 121-136. 

Duiican, R., Kopecek, J., Rejmanova, P. and Lloyd, J.B. (1983) Targeting of N-(2-hydroxypropyl)-methacrylamide copolymers to liver by incorporation of galactose residues. Biochem. Biophys. Acta 755 518-521. 

Subr, V., Strohalm, J., Ulbrich, K., Duncan, R. and Hume, Z. (1992) Polymers containing enzymatically degradable bonds, Xn. Effect of spacer structure on the rate of release of daunomycin and adriainycin from poly[N-(2-hydroxypropyl)-methacrylamide] copolymer drug carriers in vitro and antitumour activity measured in vivo. J. Controlled Rel. 18 123-132. 

Cassidy, J., Duncan, R., Morrison, G.J., Strohalm, J., et al. (1989) Activity of N-(2-hydroxypropyl)methacrylamide copolymers containing daunomycin against a rat tumour model. Biochem. Pharmacol. 38 875-880. 

Kopeckova, P. and Kopecek, J. (1990) Release of 5-aminosalicylic acid from bioadhesive N-(2-hydroxypropyl)methacrylamide copolymers by azoreductases in vitro. Makromol Chem. 191 2037-2045. 

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