Abstract 2066: Albumin-binding doxorubicin prodrug selectively activated by radiation-induced apoptotic tumor cells

Abstract

Abstract Despite the well-recognized potent anticancer effect of doxorubicin, the clinical use of doxorubicin is limited due to its dose-dependent toxicity. In this study, a novel drug delivery technology fundamentally different from the conventional tumor-targeting approaches was employed to improve the therapeutic index of doxorubicin. The prepared doxorubicin prodrug, EMC-DEVD-S-DOX, has two distinct features for effective tumor targeting: EPR effect-mediated passive targeting of tumor and extended plasma half-life by in situ albumin binding, and radiation-induced apoptosis targeting. The prodrug comprises of two important functional molecules: first, a maleimide group that allows in situ binding of the prodrug to the circulating albumin after intravenous administration; second, a DEVD motif that plays a crucial role in the activation of the prodrug through caspase-3-mediated cleavage in the apoptotic tumor cells that are exposed to radiation. As a result, EMC-DEVD-S-DOX showed a prolonged plasma half-life with selective accumulation within the tumor tissue, and was only activated and released free doxorubicin when combined with radiotherapy, thereby showing excellent synergistic effect. Our suggested drug delivery strategy completely relies on the anatomical feature of tumor vasculatures and the upregulated caspase-3 after exposure to radiation. In this reason, the genomic variations of tumor cells are unlikely to influence the efficacy of the prodrug. Considering that the conventional active tumor targeting approach is seriously challenged by the intratumor heterogeneity, EMC-DEVD-S-DOX could be an outstanding alternative for an effective cancer treatment. Citation Format: Seung Woo Chung, Kwangmeyung Kim, Seong Who Kim, In-San Kim, Sang Yoon Kim, Youngro Byun. Albumin-binding doxorubicin prodrug selectively activated by radiation-induced apoptotic tumor cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2066.