Yang Chen, Ming Hui, Li Bowen, Liu Shanshan, Chen Lihua, Zhang Tingting, Gao Yajie, He Tao, Huang Canhua, Du Zhongyan
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Department of Biotherapy, Institute of Oxidative Stress Medicine, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
J Control Release. 2024 Dec;376:659-677. doi: 10.1016/j.jconrel.2024.10.043. Epub 2024 Oct 25.
Dihydroartemisinin (DHA), a compound extracted from the herbal medicine Artemisia annua, has shown promise as a clinical treatment strategy for colorectal cancer. However, its clinical use is hindered by its low water solubility and bioavailability. A pH/glutathione (GSH) dual-responsive nano-herb delivery system (PMDC NPs) has been developed for the targeted delivery of DHA, accompanied by abundant carbon monoxide (CO) release. Due to the passive enhanced permeability and retention (EPR) effect and active targeting mediated by pHCT74 peptide binding to overexpressed α-enolase on colorectal cancer cells, the pHCT74/MOF-5@DHA&CORM-401 nanoparticles (PMDC NPs) exhibited specific targeting capacity against colorectal cancer cells. Once reaching the tumor site, the pH/GSH dual-responsive behavior of metal-organic framework-5 (MOF-5) enabled the rapid release of cargo, including DHA and CORM-401, in the acidic tumor microenvironment. Subsequently, DHA stimulated CORM-401 to release CO, which facilitated ROS-induced ferroptosis and apoptosis, leading to immunogenic cell death (ICD) and a sustained antitumor response through the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). Overall, PMDC NPs enhanced the bioavailability of DHA and exhibited outstanding therapeutic effectiveness both in vitro and in vivo, indicating their potential as a promising and feasible alternative for synergistic treatment with immunotherapy and gas therapy in the clinical management of colorectal cancer.
双氢青蒿素（DHA）是从草药青蒿中提取的一种化合物，已显示出作为结直肠癌临床治疗策略的潜力。然而，其临床应用受到低水溶性和生物利用度的阻碍。已开发出一种pH/谷胱甘肽（GSH）双响应纳米草药递送系统（PMDC NPs）用于DHA的靶向递送，并伴有大量一氧化碳（CO）释放。由于被动增强渗透和滞留（EPR）效应以及pHCT74肽与结直肠癌细胞上过表达的α-烯醇化酶结合介导的主动靶向作用，pHCT74/MOF-5@DHA&CORM-401纳米颗粒（PMDC NPs）对结直肠癌细胞表现出特异性靶向能力。一旦到达肿瘤部位，金属有机框架-5（MOF-5）的pH/GSH双响应行为能够在酸性肿瘤微环境中快速释放包括DHA和CORM-401在内的货物。随后，DHA刺激CORM-401释放CO，这促进了ROS诱导的铁死亡和凋亡，通过释放肿瘤相关抗原（TAAs）和损伤相关分子模式（DAMPs）导致免疫原性细胞死亡（ICD）和持续的抗肿瘤反应。总体而言，PMDC NPs提高了DHA的生物利用度，并在体外和体内均表现出出色的治疗效果，表明它们有潜力成为结直肠癌临床管理中免疫疗法和气体疗法协同治疗的一种有前景且可行的替代方案。
