An azo bond primary cleavage and C–C bond secondary cleavage-based polymeric β-lapachone prodrug for selective anti-cancer therapy  

一种基于偶氮键一级断裂与C-C键二级断裂释放药物的β-lapachone高分子纳米前药用于肿瘤选择性治疗

作　　者：Weidong Zhao Mengfei Zheng Hongyu Chu Jingxuan Zhang Kun Wang Chenguang Yang Na Shen Zhaohui Tang 赵唯栋;郑梦飞;褚虹宇;张景宣;王昆;杨晨光;沈娜;汤朝晖(Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China;School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China;Department of Gastrointestinal,Colorectal and Anal Surgery,China-Japan Union Hospital of Jilin University,Changchun 130033,China;Department of Pathogenbiology,State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases,College of Basic Medicine,Jilin University,Changchun 130062,China)

机构地区：[1]Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China [2]School of Applied Chemistry and Engineering,University of Science and Technology of China,Hefei 230026,China [3]Department of Gastrointestinal,Colorectal and Anal Surgery,China-Japan Union Hospital of Jilin University,Changchun 130033,China [4]Department of Pathogenbiology,State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases,College of Basic Medicine,Jilin University,Changchun 130062,China

出　　处：《Science China Materials》2025年第2期640-651,共12页中国科学(材料科学)(英文版)

基　　金：financially supported by the Ministry of Science and Technology of the People’s Republic of China (2022YFE0110200);the National Natural Science Foundation of China (52025035, 52273157, and 52073279);the Department of Science and Technology of Jilin Province (20240305041YY and 20230508102RC);the Youth Innovation Promotion Association of the Chinese Academy of Sciences (2022224)。

摘　　要：β-Lapachone (β-Lap) is a promising orthonaphthoquinone drug for cancer treatment and has been inclinical trials. Its application is constrained by the low aqueoussolubility, and severe side effects. Even prodrug designation isan effective approach to render it with tumor selectivity, it islimited by the lack of modifiable groups on β-Lap. Herein, anovel azo bond primary cleavage and carbon–carbon (C–C)bond secondary cleavage-based polymeric β-Lap prodrug(Azo-Lap NP) is designed, in which the self-immolated paraaminobenzyl linker is connected to poly(L-glutamic acid)(PGlu) via azo linkage and the responsive drug release of β-Lapagainst tumors can be achieved under high NAD(P)H:quinoneoxidoreductase 1 (NQO1) expression and low pH environmentin tumors. The effective covalent loading of β-Lap by Azo-LapNPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-LapNPs markedly reduced the side effects of β-Lap by avoidinghemolysis and the production of methemoglobin. The safety ofAzo-Lap NPs administration is validated in the antitumorexperiment of mice. In the 4T1 model, Azo-Lap NPs exhibiteda markedly higher tumor suppression rate than β-Lap. Thiswork provides an effective and safe polymeric prodrug fortumor selective delivery of β-Lap.β-lapachone (β-Lap)是一种极具潜力的邻萘醌类抗肿瘤药物,但β-Lap临床应用受限于低水溶性和严重的毒副作用.前药修饰策略可有效增强药物的肿瘤选择性,但β-Lap受限于缺乏可修饰基团.本文设计了一种新型偶氮键一级断裂和碳碳键(C-C)二级断裂的β-Lap高分子纳米前药(Azo-Lap NP),自消除的对氨基苯基连接子通过偶氮键连接聚谷氨酸,在高表达NQO1和低pH的肿瘤环境下,实现肿瘤响应性β-Lap释放.Azo-Lap NPs对β-Lap的有效共价负载可显著提高β-Lap的给药剂量,并延长药物的肿瘤停留时间.此外,Azo-Lap NPs通过避免溶血和高铁血红蛋白的产生显著降低β-Lap的毒副作用.通过小鼠抑瘤实验验证了Azo-Lap NPs安全性.在4T1模型中,Azo-Lap NPs组的抑瘤率明显高于β-Lap组.本研究为肿瘤选择性递送β-Lap提供了一种更有效且安全的高分子纳米前药.

关 键 词：β-lapachone NQO1 C-C bond cleavage polymeric nanoprodrug azo linkage 

分 类 号：R73[医药卫生—肿瘤]