Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer  

作　　者：Jiahui Zou Xuyang Xing Chao Teng Qingling Zhao Wei He Xuri Wu Yuanzheng Xia 

机构地区：[1]School of Pharmacy,China Pharmaceutical University,Nanjing 211198,China [2]School of Computer Science and Engineering,Nanjing University of Science and Technology,Nanjing 210094,China [3]School of Life Science and Technology,China Pharmaceutical University,Nanjing 211198,China [4]State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research,School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 211198,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4509-4525,共17页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.82073782 and 82241002,China);the Shanghai Science and Technology Committee(No.19430741500,China);National Key Research and Development Program of China(2018YFA0902000,China);the Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education of Jiangxi University of Traditional Chinese Medicine(zdsys-202103,China).

摘　　要：Multidrug resistance(MDR),the major mechanism by which various cancers develop specific resistance to therapeutic agents,has set up enormous obstacles to many forms of tumor chemotherapy.Traditional cocktail therapy administration,based on the combination of multiple drugs for anti-MDR chemotherapy,often suffers from inconsistent in vivo pharmacokinetic behaviors that cannot act synchronously on the lesions,leading to limited pharmacodynamic outcomes.Despite the emergence of nanomedicines,which has improved chemotherapeutic drugs’bioavailability and therapeutic effect on clinical application,these monotherapy-based nano-formulations still show poor progression in overcoming MDR.Herein,a“one stone and three birds”nanococktail integrated by a cocrystal@protein-anchoring strategy was purposed for triple-payload delivery,which paclitaxel-disulfiram cocrystal-like nanorods(NRs)were anchored with the basic protein drug Cytochrome c(Cyt C),followed by hyaluronic-acid modification.In particular,NRs were utilized as carrier-like particles to synchronously deliver biomacromolecule Cyt C into tumor cells and then promote cell apoptosis.Of note,on A549/Taxol drug-resistant tumor-bearing mice,the system with extraordinarily high encapsulation efficiency demonstrated prolonged in vivo circulation and increased tumor-targeting accumulation,significantly reversing tumor drug resistance and improving therapeutic efficacy.Our mechanistic study indicated that the system induced the apoptosis of Taxol-resistant tumor cells through the signal axis P-glycoprotein/Cyt C/caspase 3.Collectively,this nanococktail strategy offers a promising approach to improve the sensitivity of tumor cells to chemotherapeutic drugs and strengthen intractable drug-resistant oncotherapy.

关 键 词：COCKTAIL MULTIDRUG-RESISTANT Co-delivery combined therapy Cytochrome C NANOCRYSTALS 

分 类 号：R730.5[医药卫生—肿瘤]