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Co-delivery of 2-DG and V9302 via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer

Luo, Zhangyi (2019) Co-delivery of 2-DG and V9302 via a Prodrug Micellar Formulation for Synergistic Targeting of Metabolism in Cancer. Master's Thesis, University of Pittsburgh. (Unpublished)

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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. 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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Luo, Zhangyizhl117@pitt.eduZHL117
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLi, Songsol4@pitt.edusol4
Committee MemberYang, Dadyang@pitt.edudyang
Committee MemberMa, Xiaochaomxiaocha@pitt.edumxiaocha
Date: 10 April 2019
Date Type: Publication
Defense Date: 25 March 2019
Approval Date: 10 April 2019
Submission Date: 5 April 2019
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 50
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: glutamine uptake inhibitor; polymeric micelle; drug delivery
Date Deposited: 10 Apr 2019 16:40
Last Modified: 10 Apr 2019 16:40
URI: http://d-scholarship.pitt.edu/id/eprint/36370

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