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

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

作者机构：Key Laboratory of Polymer EcomaterialsChangchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China School of Applied Chemistry and EngineeringUniversity of Science and Technology of ChinaHefei 230026China Department of GastrointestinalColorectal and Anal SurgeryChina-Japan Union Hospital of Jilin UniversityChangchun 130033China Department of PathogenbiologyState Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious DiseasesCollege of Basic MedicineJilin UniversityChangchun 130062China 

出 版 物：《Science China Materials》 (中国科学(材料科学)(英文版))

年 卷 期：2025年第68卷第2期

页      面：640-651页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 07[理学] 070205[理学-凝聚态物理] 08[工学] 080501[工学-材料物理与化学] 0805[工学-材料科学与工程（可授工学、理学学位）] 100214[医学-肿瘤学] 10[医学] 0702[理学-物理学] 

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) 

主　　题：β-lapachone NQO1 C-C bond cleavage polymeric nanoprodrug azo linkage 

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.