Research Papers:

GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates

Ran Liu, Zheng Fu, Meng Zhao, Xiangqian Gao, Hong Li, Qian Mi, Pengxing Liu, Jinna Yang, Zhi Yao and Qingzhi Gao _

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Oncotarget. 2017; 8:39476-39496. https://doi.org/10.18632/oncotarget.17073

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Ran Liu1, Zheng Fu2, Meng Zhao3, Xiangqian Gao1, Hong Li4, Qian Mi1, Pengxing Liu1, Jinna Yang5, Zhi Yao2 and Qingzhi Gao1

1Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, P. R. China

2Department of Immunology, Laboratory of Immune Micro-environment, Tianjin Medical University, Tianjin 300070, P. R. China

3Department of Clinical Laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin 300040, P. R. China

4Affiliated Hospital, Logistics University of the Chinese People’s Armed Police Force, Tianjin 300162, P. R. China

5Department of Medicinal Chemistry, Gudui BioPharma Technology Inc., Huayuan Industrial Park, Tianjin 300384, P. R. China

Correspondence to:

Qingzhi Gao, email: qingzhi@tju.edu.cn

Zhi Yao, email: yaozhi@tijmu.edu.cn

Keywords: fluorine containing platinum(II) glycoconjugates, glucose transporter 1, Warburg effect, tumor targeting

Received: December 20, 2016     Accepted: March 22, 2017     Published: April 13, 2017


Increased glycolysis and overexpression of glucose transporters (GLUTs) are physiological characteristics of human malignancies. Based on the so-called Warburg effect, 18flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, we focus on the fluorine substituted series of glucose, mannose and galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-flouromalonato-platinum(II) complexes for a comprehensive evaluation on their selective tumor targeting. Besides highly improved water solubility, these sugar-conjugates presented improved cytotoxicity than oxaliplatin in glucose tranporters (GLUTs) overexpressing cancer cell lines and exhibited no cross-resistance to cisplatin. For the highly water soluble glucose-conjugated complex (5a), two novel in vivo assessments were conducted and the results revealed that 5a was more efficacious at a lower equitoxic dose (70% MTD) than oxaliplatin (100% MTD) in HT29 xenograft model, and it was significantly more potent than oxaliplatin in leukemia-bearing DBA/2 mice as well even at equimolar dose levels (18% vs 90% MTD). GLUT inhibitor mediated cell viability analysis, GLUT1 knockdown cell line-based cytotoxicity evaluation, and platinum accumulation study demonstrated that the cellular uptake of the sugar-conjugates was regulated by GLUT1. The higher intrinsic DNA reactivity of the sugar-conjugates was confirmed by kinetic study of platinum(II)-guanosine adduct formation. The mechanistic origin of the antitumor effect of the fluorine complexes was found to be forming the bifunctional Pt-guanine-guanine (Pt-GG) intrastrand cross-links with DNA. The results provide a rationale for Warburg effect targeted anticancer drug design.

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