Synthesis of Long-Circulating, Backbone Degradable HPMA Copolymer-Doxorubicin Conjugates and Evaluation of Molecular-Weight-Dependent Antitumor Efficacy

Backbone degradable, linear, multiblock N‐(2‐hydroxypropyl)methacrylamide (HPMA) copolymer–doxorubicin (DOX) conjugates are synthesized by reversible addition–fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol‐ene click reaction. The examination of molecular‐weight‐dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second‐generation, higher molecular weight conjugates when compared with traditional HPMA copolymer–DOX conjugates. The examination of body weight changes during treatment indicates the absence of non‐specific adverse effects. Multiblock, degradable, linear HPMA copolymer–doxorubicin conjugates have an enhanced intravascular half‐life. This provides for sustained extravasation into the tumor tissue with concomitant increase in therapeutic efficacy against human ovarian carcinoma xenografts in nude mice.