In Vitro Synergistic Action of Geldanamycin- and Docetaxel-Containing HPMA Copolymer-RGDfK Conjugates Against Ovarian Cancer

Abstract

This study describes the synthesis, characterization, and in vitro evaluation of a combination therapy utilizing HPMA copolymer-RGDfK conjugates. HPMA copolymer-RGDfK conjugates bearing either aminohexylgeldanamycin or docetaxel were synthesized and characterized. Stability was evaluated in physiologically relevant media. Binding to αvβ3 integrins on the surface of ovarian cancer cells was assessed. Cytotoxicity towards ovarian cancer cells was evaluated and the ability of the conjugates in combination to induce cell death was assessed by combination index analysis. Conjugates bearing aminohexylgeldanamycin were more stable and exhibited slower drug release than those bearing docetaxel. Both conjugates demonstrated the ability to bind specifically to αvβ3 integrins. In combination, HPMA copolymer-RGDfK conjugates demonstrated marked synergism as compared to their non-targeted counterparts and free drug controls. HPMA copolymer-RGDfK conjugates bearing aminohexylgeldanamycin and docetaxel induce cytotoxicity in vitro in a synergistic manner, suggesting their potential as a promising combination therapy for ovarian cancer.

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