ROS/Enzyme Dual-Responsive Drug Delivery System for Targeted Colorectal Cancer Therapy: Synergistic Chemotherapy, Anti-Inflammatory, and Gut Microbiota Modulation

作者：Xin Zhang, Ruonan Lian, Bingbing Fan, Lei Meng, Pengxia Zhang, Yu Zhang, Weitong Sun · 发表于：Pharmaceutics · 年份：2025 · DOI：10.3390/pharmaceutics17070940 · 被引用次数：8 · 研究领域：Curcumin's Biomedical Applications、Cancer Research and Treatments、Nanoparticle-Based Drug Delivery

Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality, driven by chronic inflammation, gut microbiota dysbiosis, and complex tumor microenvironment interactions. Current therapies are limited by systemic toxicity and poor tumor accumulation. This study aimed to develop a ROS/enzyme dual-responsive oral drug delivery system, KGM-CUR/PSM microspheres, to achieve precise drug release in CRC and enhance tumor-specific drug accumulation, which leverages high ROS levels in CRC and the β-mannanase overexpression in colorectal tissues. Methods: In this study, we synthesized a ROS-responsive prodrug polymer (PSM) by conjugating polyethylene glycol monomethyl ether (mPEG) and mesalazine (MSL) via a thioether bond. CUR was then encapsulated into PSM using thin-film hydration to form tumor microenvironment-responsive micelles (CUR/PSM). Subsequently, konjac glucomannan (KGM) was employed to fabricate KGM-CUR/PSM microspheres, enabling targeted delivery for colorectal cancer therapy. The ROS/enzyme dual-response properties were confirmed through in vitro drug release studies. Cytotoxicity, cellular uptake, and cell migration were assessed in SW480 cells. In vivo efficacy was evaluated in AOM/DSS-induced CRC mice, monitoring tumor growth, inflammatory markers (TNF-α, IL-1β, IL-6, MPO), and gut microbiota composition. Results: In vitro drug release studies demonstrated that KGM-CUR/PSM microspheres exhibited ROS/enzyme-responsive release profiles. CUR/PSM micell...