The Comparison of In Vivo Properties of Water-Soluble HPMA-Based Polymer Conjugates with Doxorubicin Prepared by Controlled RAFT or Free Radical Polymerization

Two conjugates of anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond to the polymer carrier based on water-soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesized and their properties were compared, namely their behavior in vivo. The polymer carriers differed in dispersity due to different methods of synthesis; the carrier with relatively high dispersity (HD) was prepared by free radical polymerization (Mw = 29 900 g/mol, Ð = 1.75) and the carrier with low dispersity (LD) by controlled radical polymerization (Mw = 30 000 g/mol, Ð = 1.13). Both polymer-Dox conjugates showed prolonged blood circulation and tumor accumulation of the drug in comparison with the free drug; e.g. the tumor-to-blood ratio for the polymer-bound Dox was 3-5 times higher. The LD polymer-Dox conjugate exhibited moderately higher tumor accumulation than the HD one at a dose of 1 x 15 mg Dox (eq.)/kg. Also, their anti-tumor activity did not differ when injected at this dose. However, the increase of the dose to 1 x 25 mg Dox (eq.)/kg resulted in the enhanced therapeutic activity of the conjugates, especially of the LD one with 100 % of long-term survivals. The dispersity of polymer drug carriers influenced the tumor accumulation rate, which affected the overall anti-cancer activity of polymer-drug conjugates.