Developing an anticancer copper(II) pro-drug based on the nature of cancer cell and human serum albumin carrier IIA subdomain: mouse model of breast cancer
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Yi Gou1,*, Yao Zhang1,*, Jinxu Qi1, Shifang Chen1, Zuping Zhou2, Xiaoyang Wu3, Hong Liang1, Feng Yang1,2
1State Key Laboratory for The Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, Guangxi Normal University, Guilin, Guangxi, China
2Guangxi University Key Laboratory of Stem Cell and Pharmaceutical Biotechnology, Guangxi Normal University, Guilin, Guangxi, China
3Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA
*These authors have contributed equally to this work
Hong Liang, email: [email protected]
Feng Yang, email: [email protected]
Keywords: copper pro-drug, human serum albumin, tumor targeting, therapeutic effect
Received: April 05, 2016 Accepted: July 27, 2016 Published: August 22, 2016
Human serum albumin (HSA)-based drug delivery systems are promising for improving delivery efficiency, anticancer activity and selectivity of anticancer agents. To rationally guide to design HSA carrier for anticancer metal agent, we built a breast mouse model on developing anti-cancer copper (Cu) pro-drug based on the nature of IIA subdomain of HSA carrier and cancer cells. Thus, we first synthesized a new Cu(II) compound derived from tridentate (E)-N'-(5-bromo-2-hydroxybenzylidene)benzohydrazide Schiff base ligand (HL) containing 2 potential leaving groups [indazole (Ind) and NO3−], namely, [Cu(L)(Ind)NO3]. Structural analysis of the HSA complex showed that Cu(L)(Ind)(NO3) could bind to the hydrophobic pocket of the HSA IIA subdomain. Lys199 and His242 coordinate with Cu2+ by replacing the indazole and NO3 ligands of [Cu(L)(Ind)NO3]. The release behavior of the Cu compound from the HSA complex is different at different pH levels. [Cu(L)(Ind)NO3] can enhance cytotoxicity by 2 times together with HSA specifically in cancer cells but has no such effect on normal cells in vitro. Importantly, our in vivo results showed that the HSA complex displayed increased selectivity and capacity to inhibit tumor growth and was less toxic than [Cu(L)(Ind)NO3] alone.
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