Synthesis and characterization of N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer-emetine conjugates

The plant alkaloid emetine has considerable potential as an antitumor agent, but early attempts to develop the compound clinically failed due to unacceptable dose limiting toxicity and poorly reproducible results. This study reports the synthesis and characterization of novel N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates containing emetine. The drug was linked to the polymer via biodegradable (Gly-Phe-Leu-Gly) and non-degradable (Gly-Gly) peptidyl linkers. HPMA-Gly-Gly emetine conjugate was found to contain 8% (w/w) of bound emetine, while emetine loading of HPMA-Gly-Phe-Leu-Gly-emetine was found to be 19% (w/w). Due to the change in cellular pharmacokinetics, polymer conjugates are invariably less toxic than free drug, in vitro and HPMA copolymer-emetine conjugates were no exception. Conjugates containing the biodegradable Gly-Phe-Leu-Gly linker displayed an IC50 of 90 mu g/mL towards L1210 leukemia cells which is 225 less toxic than free emetine (IC50 = 0.4 mu g/mL). Against B16F10 melanoma the conjugate was 60 times less toxic than free drug (IC50 of 300 and 5 mu g/mL respectively). In contrast, the conjugate containing a non-biodegradable (Gly-Gly) linker showed very low or no activity in vitro. Although the conjugates showed no significant effect on the rate of tumor growth, the HPMA-Gly-Gly-emetine prodrug had a significant effect on the survival time of animals bearing L1210 tumors. Here we describe the first polymer conjugates containing emetine. Further studies are warranted to document the spectrum of antitumor activity, dose-limiting toxicity and pharmacokinetics of HPMA copolymer-emetine in vivo.