Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Acta Biomater. 2023 Oct 15;170:273-287. doi: 10.1016/j.actbio.2023.08.021. Epub 2023 Aug 18.
The primary cause of cisplatin resistance in liver cancer is reduced intracellular drug accumulation and altered DNA repair/apoptosis signaling. Existing strategies to reverse cisplatin resistance have limited efficacy, as they target individual factors. This study proposes a drug delivery system consisting of a cisplatin core, a silica shell with a tetra-sulfide bond, and a PEG-coated surface (Core/shell-PGCN). The system is designed to consume glutathione (GSH) and reduce cisplatin excretion from cells, thereby overcoming acquired cisplatin resistance. In addition, Core/shell-PGCN incorporates PTC-209 (Core/shell-PGCN@PTC-209), a Bmi1 inhibitor that suppresses liver cancer stem cells (CSC), to mitigate DNA repair/apoptosis signaling and reverse intrinsic cisplatin resistance. In vivo and in vitro results demonstrate that Core/shell-PGCN@PTC-209 can comprehensively regulate GSH and CSC, reverse intrinsic and acquired cisplatin resistance, and enhance the efficacy of cisplatin in treating liver cancer. This "inner cultivation, outer action" approach may offer a new strategy for reversing cisplatin resistance in liver cancer. STATEMENT OF SIGNIFICANCE: Cisplatin resistance is widely observed in liver cancer (HCC) chemotherapy, with two mechanisms identified: acquired and intrinsic. Most strategies aimed at overcoming cisplatin resistance focus on a single perspective. This study introduces a core-shell drug delivery system (DDS) combined with HCC stem cell inhibitors, which can effectively address cisplatin resistance in HCC by targeting both acquisition and internality. Specifically, the core-shell drug delivery system can impede cisplatin efflux by neutralizing the acquired resistance factor (GSH), thus overcoming acquired resistance. Additionally, HCC stem cell inhibitors can reverse intrinsic resistance by inhibiting HCC stem cells. Therefore, this study contributes to the application of DDS in combating drug resistance in HCC and enhances its potential for clinical implementation.
原发性肝癌顺铂耐药的主要原因是细胞内药物蓄积减少和 DNA 修复/凋亡信号改变。现有逆转顺铂耐药的策略疗效有限，因为它们针对的是单个因素。本研究提出了一种由顺铂核心、带有四硫键的二氧化硅壳和聚乙二醇涂层表面组成的药物递送系统（Core/shell-PGCN）。该系统旨在消耗谷胱甘肽（GSH）并减少细胞内顺铂的排泄，从而克服获得性顺铂耐药。此外，Core/shell-PGCN 还包含了一种 Bmi1 抑制剂 PTC-209（Core/shell-PGCN@PTC-209），可以抑制肝癌干细胞（CSC），从而减轻 DNA 修复/凋亡信号并逆转内在的顺铂耐药性。体内和体外结果表明，Core/shell-PGCN@PTC-209 可以全面调节 GSH 和 CSC，逆转内在和获得性顺铂耐药性，并增强顺铂治疗肝癌的疗效。这种“内培外治”的方法可能为逆转肝癌顺铂耐药提供一种新策略。
