Increased therapeutic efficacy and reduced toxicity of doxorubicin linked to pyran copolymer via the side chain of the drug.

Doxorubicin was covalently linked to divinyl ether-maleic anhydride copolymer (pyran copolymer) in its polycarboxylate form via the methylketone side chain through a nucleophilic substitution reaction of the 14-bromo derivative of the drug. The drug conjugated to the synthetic polyanionic polymer was tested for antitumor activity in a range of experimental murine tumor systems. When administered ip to mice bearing ip implanted tumors (P388 leukemia or macrophage tumor J774), the polymer-linked drug was superior to free doxorubicin and daunorubicin in increasing the life span of treated animals. Treatment with the conjugate also resulted in an improvement in survival time of mice bearing ascitic M50 tumor, although the effects of a single dose of free drug, in the range of maximum tolerated doses, were marginal. When given iv, the conjugate was more effective than free drug against systemic Gross leukemia. The therapeutic advantage of the polymer-linked doxorubicin over free drug was more marked when a multiple treatment schedule was used. Studies in vitro showed that the drug following covalent fixation to the polymer had only marginally decreased cytotoxicity against HeLa and P388 cells when compared with that of free anthracycline. This effect paralleled the lack of reduction in in vivo potency. Moreover, the covalent linkage of the drug to synthetic polymer reduced drug toxicity. This effect was more marked with the ip route of administration than with the iv route.