Using N-(2-hydroxypropyl) methacrylamide copolymer drug bioconjugate as a novel approach to deliver a Bcl-2-targeting compound HA14-1 in vivo

Bcl-2 plays a critical role in regulation of apoptosis and tumor pathogenesis; thus it's a good therapeutic target for cancer. Small compounds blocking Bcl-2 have been identified but their efficacy in vivo has hardly been demonstrated. We developed water-soluble N-(2-hydroxypropyl) methacrylamide ( HPMA) copolymers containing a Bcl-2 targeting compound HA14-1. Their efficacy was confirmed in cell lines, and tested in a tumor xenograft model. Intraperitoneal injected copolymer HA14-1 bioconjugates suppressed tumor growth by 50%. Using FITC as a marker to trace biodistribution, we demonstrated that the concentration of the copolymer was sufficient to induce apoptosis. This was confirmed by the presence of activated caspase 9 in tumor treated with the copolymer HA14-1 bioconjugate, but not in normal organs or tumor treated with a control polymer. No toxicity was observed in liver and kidney, where copolymers are excreted. The HPMA copolymer is thus a promising strategy for in vivo delivery of Bcl-2-targeting compounds to solve their poor solubility problem and to enhance tumor selectivity.