The pharmacokinetics of polymer-bound adriamycin

Adriamycin (ADR) covalently bound to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers via biodegradable (Gly-Phe-Leu-Gly) oligopeptide sequences shows antitumour activity against model tumours in vivo. In this study we have examined the distribution of ADR bound to such HPMA copolymers following intravenous administration to mice (ADR concentration 5 mg/kg). An established fluorimetric HPLC method was used to measure levels of free ADR in plasma and tissue samples, and a new technique was developed to quantitate levels of polymer-bound anthracycline. The high initial levels of free ADR in plasma observed following administration of free drug were absent in the case of polymer-bound ADR, and the subsequently high levels of free ADR seen in other tissues were also abolished. In contrast, the circulating half-life of HPMA copolymer-ADR was approximately 15 times longer than that of the free drug. The initial peak level of free ADR in the heart was reduced 100-fold following administration of drug-conjugate. These alterations in pharmacokinetics may account for the decreased toxicity and improved efficacy reported previously.