Design, Synthesis, and Biological Evaluation of a Novel Gedatolisib−Phospholipid Conjugate and Liposomal Formulations Based Thereon

Abstract Herein, we report the synthesis and biological evaluation of the first phospholipid prodrug of gedatolisib, a dual PI3K/mTOR inhibitor, and liposomal nanoparticles based on this conjugate. The liposomes were designed for selective cleavage by phospholipase A2, enabling the release of the active drug from the gedatolisib−phospholipid conjugate. Compared with free gedatolisib, the liposomal formulation demonstrated cytotoxicity that was 2−3 orders of magnitude lower across several cancer cell lines. In vivo studies using the EMT6 breast cancer model showed that the liposomal prodrug exhibited superior antitumor efficacy while being substantially less hepatotoxic than free gedatolisib, which displayed negligible antitumor activity. This phospholipid conjugation strategy represents a promising approach for potentially improving the therapeutic index of gedatolisib.