Synthesis of antitumor‐active conjugates of adriamycin or daunomycin with the copolymer of divinyl ether and maleic anhydride

TLDR: An antitumor activity of the polymeric conjugate better than that of the free drug was also observed in vivo with DM and such a polymeric effect can be attributed either to the change in body distribution, the difference in pharmacokinetics, or the slow drugrelease.

Abstract: Polymeric conjugates of adriamycin (ADR) (2) or daunomycin (DM) (3) were synthesized by reaction of the drugs with the copolymer of divinyl ether and maleic anyhdride (DIVEMA) (1). The content of ADR moieties in the DIVEMA conjugate (4) could be varied depending on the reaction conditions up to 35,8 wt.-%. Considering the low toxicity and the high possibility of renal excretion, DIVEMA with Mw of 7000 and Mw/Mn = 1,6 was used for the conjugation. The rate of drug release from the conjugate was determined under physiological conditions by reversed phase HPLC. Within 14 days only 15% of the attached ADR was released from conjugate 4. The antitumor activity of the conjugates was tested in vitro and in vivo against mouse P388 leukemia. Conjugate 4 proved to be 28 times less active than ADR in vitro, which could be explained from the slow drug-release. On the contrary 50% of the leukemic mice treated by 4 survived more than 60 days, whereas no mice given ADR alone or the admixture of ADR and DIVEMA survived 30 days. An antitumor activity of the polymeric conjugate better than that of the free drug was also observed in vivo with DM. Such a polymeric effect can be attributed either to the change in body distribution, the difference in pharmacokinetics, or the slow drugrelease.