MACROMOLECULAR PRODRUGS FOR USE IN TARGETED CANCER-CHEMOTHERAPY - MELPHALAN COVALENTLY COUPLED TO N-(2-HYDROXYPROPYL) METHACRYLAMIDE COPOLYMERS

Although there are approximately thirty antitumour agents in clinical use recent progress has been relatively slow in the identification of novel compounds with improved therapeutic index. Macromolecular drug-carriers afford the potential to permit controlled release and site-specific delivery of those antitumour agents whose activity may be limited by their inherent toxicity and/or lack of tumour-specific deposition. In this study N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesised to contain melphalan (ME) or sarcolysin (SE) (1 - 10 wt%) linked to the polymer back-bone (P) via peptide side-chains e.g. P-Gly-ME, P-Gly-Gly-ME, P-Gly-Leu-Gly-ME, P-Gly-Phe-Gly-ME and P-Gly-Phe-Leu-Gly-ME. ME release during incubation with isolated rat liver lysosomal enzymes was dependent on the amino acid composition of the side-chain used. Cytotoxicity measured in vitro towards Walker sarcoma was dependent on the peptide spacer and ME content of the polymer, and likewise those cojugates which showed the fastest rates of cleavage by lysosomal enzymes displayed greatest antitumour activity against Walker sarcoma in vivo. Administration (i.p.) of biodegradable polymer-SE conjugates on day 1 (5 mg/kg) after inoculation of 10(6) Walker cells (s.c.) reduced or prevented establishment of tumours. Similarly, treatment of established Walker sarcoma (approximately 200 mm2 in area) with polymer conjugate of SE or ME caused a reduction in tumour size. However, it was found that free drug at equivalent dose was also effective against Walker sarcoma in vivo and the therapeutic index of polymer conjugated drug was not appreciably greater than that of the free drug and was dependent on the dosing regime. The pharmacokinetics of [H-3]melphalan and I-125-labelled HPMA copolymer-ME was followed in animals bearing established Walker tumours. Macromolecular conjugate delivered substantially more radioactivity to the tumour than free drug. Although this altered pharmacokinectics must contribute to tumour specific drug activity, the precise mechanism of action of polymer-bound melphalan remains unclear. Preliminary experiments showed a significant increase in the number of macrophages and T and B lymphocytes found in tumours taken from animals 4 days after administration of polymer conjugate when compared to those from untreated or melphalan treated animals.