(555g) Co-Delivery of 2-DG and V9302 Via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancers

The unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported ASCT2 amino acid transporter inhibitor which shows promising antitumor activity by blocking glutamine uptake. However, its poor solubility in aqueous solutions and tumor cells’ compensatory metabolic shift to glucose metabolism may limit the antitumor efficacy of V9302. 2-Deoxyglucose (2-DG), a derivative of glucose, has been developed as a potential antitumor agent through inhibiting glycolysis in tumor cells. In order to achieve enhanced antitumor effect by inhibiting both metabolic pathways, a 2DG prodrug-based micellar carrier (POEG-p2DG) was developed. POEG-p2DG well retained the pharmacological activity of 2-DG in vitro and in vivo. More importantly, POEG-p2DG self-assembled to form micelles that were capable of loading V9302 to achieve co-delivery of 2-DG and V9302. V9302-loaded POEG-p2DG micelles were small in sizes (~10nm) and showed a slow kinetics of drug release. In addition, V9302-loaded POEG-p2DG micelles exhibited improved cytotoxicity towards tumor cells compared to free V9302. These results suggest that POEG-p2DG prodrug micelles may serve as a dual functional carrier for V9302 to achieve synergistic targeting of metabolism in cancers.