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Co-Delivery of 2-Dg and V9302 Via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer

39 Pages Posted: 30 Oct 2019 First Look: Accepted

See all articles by Zhangyi Luo

Zhangyi Luo

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - University of Pittsburgh Cancer Institute

Jieni Xu

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences; University of Pittsburgh - University of Pittsburgh Cancer Institute

Jingjing Sun

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences; University of Pittsburgh - University of Pittsburgh Cancer Institute

Haozhe Huang

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - University of Pittsburgh Cancer Institute

Weina Ma

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - University of Pittsburgh Cancer Institute

Zhuoya Wan

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences; University of Pittsburgh - University of Pittsburgh Cancer Institute

Ziqian Zhang

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - University of Pittsburgh Cancer Institute

Yang Wu-yue Liu

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - University of Pittsburgh Cancer Institute

Song Li

University of Pittsburgh - Center for Pharmacogenetics; University of Pittsburgh - Department of Pharmaceutical Sciences; University of Pittsburgh - University of Pittsburgh Cancer Institute

Abstract

The unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported inhibitor of ASCT2 amino acid transporter 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 2-DG prodrug-based micellar carrier (POEG-p-2DG) was developed. POEG-p2DG well retained the pharmacological activity of 2-DG in vitro and in vivo, More importantly, POEG-p-2DG could self-assemble 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), showed a slow kinetics of drug release and demonstrated targeted delivery to tumor. In addition, V9302 loaded POEG-p-2DG micelles exhibited improved anti-tumor efficacy both in vitro and in vivo with decreased toxicity compared to free drug combination. Interestingly, 2-DG treatment further decreased the glutamine uptake when combined with V9302, likely due to inhibition of ASCT2 glycosylation. 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.

Keywords: V9302, 2-DG, Cancer metabolism, Co-delivery, Prodrug micelles

Suggested Citation

Luo, Zhangyi and Xu, Jieni and Sun, Jingjing and Huang, Haozhe and Ma, Weina and Wan, Zhuoya and Zhang, Ziqian and Liu, Yang Wu-yue and Li, Song, Co-Delivery of 2-Dg and V9302 Via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer. Available at SSRN: https://ssrn.com/abstract=3474483

Zhangyi Luo

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Jieni Xu

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Jingjing Sun

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Haozhe Huang

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Weina Ma

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Zhuoya Wan

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences

Pittsburgh, PA 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Ziqian Zhang

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Yang Wu-yue Liu

University of Pittsburgh - Center for Pharmacogenetics

Pennsylvania, 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute

Pittsburgh, PA 15260
United States

Song Li (Contact Author)

University of Pittsburgh - Center for Pharmacogenetics ( email )

Pennsylvania, 15261
United States

University of Pittsburgh - Department of Pharmaceutical Sciences ( email )

Pittsburgh, PA 15261
United States

University of Pittsburgh - University of Pittsburgh Cancer Institute ( email )

Pittsburgh, PA 15260
United States

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