Poly(carboxylic acid) polymers as carriers for anthracyclines

Abstract

Anthracycline-poly(carboxylic acid) polymer conjugates can be easily prepared in alkalinized aqueous media by a process involving a reaction of 14-bromo derivatives of the drug carrying the methylketone side chain. The method can be applied to a variety of poly(carboxylic acid) polymers. Following i.v. administration, the drug potency and efficacy was found to depend on the molecular weight of the polymer. Using pyran copolymer as carrier, a critical influence of the polymer itself on the overall efficacy of the conjugate was observed. The understanding of the in vivo interaction between drug and polymer and of the mechanism of action of drug-polymer conjugates should establish guidelines for future attempts to optimize antitumor efficacy. Although an increased selectivity in drug targeting can be achieved, in theory, by the attachment of specific targeting moieties, the preclinical evaluation of drug-poly(carboxylic acid) polymer conjugates themselves indicated therapeutic advantages over free drug. Reduction of systemic drug toxicity and, at least in selected tumor systems, increased efficacy implies improved drug delivery. In particular, the toxicologie and pharmacologie profile of doxorubicin-poly( l-aspartic acid) conjugate warrants a clinical evaluation.