title: ROS-triggered and regenerating anticancer nanosystem: an effective strategy to subdue tumor's multidrug resistance.
abstract: Drug delivery strategies utilizing tumor microenvironment are recognized as a critical doorway to overcome multidrug resistance (MDR). However, the variability of tumor microenvironment at different disease stages would definitely minimize stimuli generation and eventually the therapeutic effects of these stimuli sensitive systems. Herein, we report a unique reactive oxygen species (ROS) triggered nanosystem that can replenish the ROS upon disassembly to maintain its high level. This was accomplished by a new amphiphilic polymer (TBH) composed of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS), hyaluronic acid (HA) and arylboronic ester. As a linker of TPGS to HA, arylboronic ester could efficiently degrade in response to ROS resulting in dismantling of nanosystem followed by rapid release of TPGS. Owing to ROS inducing activity of TPGS with mitochondrial respiratory complex II, ROS regeneration was observed for TBH nanosystem both in MCF-7/ADR cells and tumor tissues xenografted with MCF-7/ADR cells. Furthermore, doxorubicin-loaded TBH nanosystem (DOX-TBH) revealed higher drug cytotoxicity due to enhanced retention effect on account of ROS triggered DOX release and P-gp inhibitory mechanism of TPGS. Moreover, HA significantly improved tumor targeting capability of DOX-TBH, while ROS based triggering and regenerating mechanism lead to marked inhibition of the tumor growth in the xenograft MCF-7/ADR tumor-bearing nude mice.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Zhigui
authors.initials: Z
authors.lastname: Su
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Minglei
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Yanyu
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: zongcpu@126.com.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Zong
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China; College of Pharmacy, Government College University Faisalabad, Faisalabad, Pakistan.
authors.forename: Sajid
authors.initials: S
authors.lastname: Asghar
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Science, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China.
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Huipeng
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: pingqn@cpu.edu.cn.
authors.forename: Qineng
authors.initials: Q
authors.lastname: Ping
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D042963:Electron Transport Complex II; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D049329:Nanostructures / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D011108:Polymers; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D042963:Electron Transport Complex II
keywords: Multidrug resistance; ROS-triggered and regenerating; Reactive oxygen species; Targeted drug delivery nanosystem; Tumor microenvironment