Glutathione-depleted cyclodextrin pseudo-polyrotaxane nanoparticles for anti-inflammatory oxaliplatin(Ⅳ) prodrug delivery and enhanced colorectal cancer therapy  

作　　者：Wenjia Wang Xingyue He Xiaojie Wang Tiantian Zhao Osamu Muraoka Genzoh Tanabe Weijia Xie Tianjiao Zhou Lei Xing Qingri Jin Hulin Jiang 

机构地区：[1]State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China [2]Faculty of Pharmacy Kinki University,Higashiosaka,Osaka 577-8502,Japan [3]State Key Laboratory of Natural Medicines(SKLNM)and Department of Medicinal Chemistry,School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China [4]School of Pharmacy,Hangzhou Medical College,Hangzhou 311399,China [5]College of Pharmacy,Yanbian University,Yanji 133002,China

出　　处：《Chinese Chemical Letters》2024年第4期280-286,共7页中国化学快报（英文版）

基　　金：financially supported by the National Natural Science Foundation of China (Nos.82020108029, 82073398);supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions and the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University (No.SKLNMZZ202021);the"111"Project from the Ministry of Education of China;the State Administration of Foreign Experts Affairs of China (No.B16046);Double First-Rate construction plan of China Pharmaceutical University (Nos.CPU2018GY06,CPU2022QZ18);China Postdoctoral Science Foundation (Nos.2021M703598, 2022M720173);Jiangsu Funding Program for Excellent Postdoctoral Talent and International Postdoctoral Exchange Fellowship Program 2022。

摘　　要：Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.

关 键 词：OXALIPLATIN Glutathione depletion Tetravalent platinum prodrug Synergistic therapy Colorectal cancer 

分 类 号：R943[医药卫生—药剂学] TB383.1[医药卫生—药学]