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 du e to unacceptable dose limiting toxicity and poorly reproducible resul ts. 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, whil e emetine loading of HPMA-Gly-Phe-Leu-Gly-emetine was found to be 19% (w/w). Due to the change in cellular pharmacokinetics, polymer conjuga tes are invariably less toxic than free drug, in vitro and HPMA copoly mer-emetine conjugates were no exception. Conjugates containing the bi odegradable Gly-Phe-Leu-Gly linker displayed an IC50 of 90 mu g/mL tow ards L1210 leukemia cells which is 225 less toxic than free emetine (I C50 = 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). I n contrast, the conjugate containing a non-biodegradable (Gly-Gly) lin ker showed very low or no activity in vitro. Although the conjugates s howed no significant effect on the rate of tumor growth, the HPMA-Gly- Gly-emetine prodrug had a significant effect on the survival time of a nimals bearing L1210 tumors. Here we describe the first polymer conjug ates containing emetine. Further studies are warranted to document the spectrum of antitumor activity, dose-limiting toxicity and pharmacoki netics of HPMA copolymer-emetine in vivo.