Targetable polymeric prodrugs

Abstract

N- (2-Hydroxypropyl) methacrylamide (HPMA) copolymers containing oligopeptide side-chains terminating in anticancer drugs (daunomycin, adriamycin) have been synthesized. The bond between the drug and the carrier was stable in the bloodstream, but was cleaved intracellularly on exposure to the lysosomal cysteine proteinases. HPMA copolymers have also been modified with targeting moieties: galactosamine, which targets the conjugate to hepatocytes; anti θ antibodies recognizing θ alloantigen expressed on immunocompetent lymphocytes; and fucosylamine, since there is a receptor on mouse leukemia L1210 cells that recognizes and binds this carbohydrate moiety. In vitro and in vivo experiments demonstrated preferential interaction of modified HPMA copolymers with the respective target cells. Subsequent experiments were performed to test the pharmacological activity of anticancer polymeric prodrugs in vivo against L1210 leukemia in DBA 2 mice. Two localizations of tumor were chosen — intraperitoneal and subcutaneous. In both cases experimental animals were treated intraperitoneally with free drug or drug-HPMA copolymer conjugates. HPMA copolymers containing anticancer drugs have shown therapeutic effect only when the oligopeptide sequence between the drug and the polymeric carrier was biodegradable . Polymeric products produced increased life span and an increased number of long term survivors depending on the structure of the conjugate (i.e. presence of biodegradable side-chains or targeting moieties), timing of administration and number of doses. From the data presented it can be concluded that targetable anticancer polymeric prodrugs may be useful clinically.