title: Mannose-conjugated platinum complexes reveals effective tumor targeting mediated by glucose transporter 1.
abstract: Despite numerous studies that report the glucose derived glycoconjugates as antitumor candidates, using mannose as sugar motif for specific tumor targeting remains less studied. In this research, two novel mannose-conjugated platinum complexes 4a and 4b that target the Warburg effect were designed, synthesized and evaluated for their antitumor activities in vitro and in vivo. Compared with oxaliplatin, both complexes exhibited substantial enhancement in water solubility as well as excellent or comparative cytotoxicity in six human cancer cell lines. Cytotoxicity assessments on Glucose transporter 1 (GLUT1) down-regulated or overexpressed cells and platinum accumulation study demonstrated that cellular uptake of compound 4a was regulated by GLUT1. In particular, 4a induced apoptosis in HT29 cells by suppressing expression of Bcl-2 and Bcl-XL, which preliminary explained the mechanism origin of antitumor effect. As indicated by its maximum tolerated dose-finding assay and in vivo anticancer activity, compound 4a exhibits better safety and efficacy profile than oxaliplatin. The findings of this study indicate the possibility of subjecting mannose-conjugated platinum complexes as lead compounds for further preclinical evaluation.
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.affiliation: Affiliated Hospital, Logistics University of the Chinese People's Armed Police Force, No. 220, Cheng-Lin Road, Hedong District, Tianjin 300162, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Gudui BioPharma Technology Inc., 5 Lanyuan Road, Huayuan Industrial Park, Tianjin 300384, PR China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Gao
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Mi
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China. Electronic address: zhaohongxia@tju.edu.cn.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China. Electronic address: qingzhi@tju.edu.cn.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry; D015195:Drug Design; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D008358:Mannose / Q000737:chemistry*; D058990:Molecular Targeted Therapy / Q000379:methods; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D017671:Platinum Compounds / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D027342:Excitatory Amino Acid Transporter 2; D017671:Platinum Compounds; D008358:Mannose
keywords: Glucose transporter 1; Mannose-conjugated platinum(II) complexes; Tumor targeting; Warburg effect