Design of Pt（IV） Prodrug by Targeting Epigenetic Alterations and Binding Human Serum Albumin for Drug Delivery
作者单位：Department of Chemical Biology and Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics School of Pharmacy Tianjin Medical University
会议名称：《第十届全国化学生物学学术会议》
会议日期：2017年
学科分类：100702[医学-药剂学] 1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100602[医学-中西医结合临床] 10[医学]
基 金：supported by the National Natural Science Foundation of China (No.21371135) the Tianjin Municipal Natural Science Foundation (No.17JCZDJC33100)
关 键 词：Epigenetics ICLs HDACs Prodrug Platinum(IV)
摘 要：Aberrant epigenetic alterations of tumor suppressor genes have been recognized as a driving force in cancer. Histone deacetylases（HDACs）, for example, are promising targets for cancer due to their crucial involvement in epigenetic and cellular signaling[1]. HDACs modulate the expression and functions of DNA repair proteins which remove DNA interstrand crosslinks（ICLs） and control the accessibility of chromatin. Manipulating ICL repair with HDAC inhibition can provide an effective strategy for ICL-inducers, such as platinum-based agents. Herein, we report an asymmetrical Pt（IV） prodrug PhB-Pt（IV）-18 C by combined HDAC inhibition, human serum albumin（HSA） binding, DNA cross-link-triggered apoptosis for synergistic chemotherapy and drug delivery. PhB-Pt（IV）-18 C effectively kills cisplatin-resistant human lung cancer cells with an up to 50-fold increase in growth inhibition compared with cisplatin. The presence of an octodecane tail can tune the cellular uptake and the cytotoxicity, and can allow binding with HSA for drug delivery. Additionally, PhB-Pt（IV）-18 C can inhibit expression of HDAC, arrest cell cycle,and induce apoptosis. These results demonstrate the combination strategy to be a valuable route for additional preclinical studies.