Chen Lihua, Ming Hui, Li Bowen, Yang Chen, Liu Shanshan, Gao Yajie, Zhang Tingting, Huang Canhua, Lang Tingyuan, Yang Zhuo
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, P. R. China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, P. R. China.
Small. 2024 Aug 5:e2403869. doi: 10.1002/smll.202403869.
Cancer metastasis poses significant challenges in current clinical therapy. Osthole (OST) has demonstrated efficacy in treating cervical cancer and inhibiting metastasis. Despite these positive results, its limited solubility, poor oral absorption, low bioavailability, and photosensitivity hinder its clinical application. To address this limitation, a glutathione (GSH)-responded nano-herb delivery system (HA/MOS@OST&L-Arg nanoparticles, HMOA NPs) is devised for the targeted delivery of OST with cascade-activatable nitric oxide (NO) release. The HMOA NPs system is engineered utilizing enhanced permeability and retention (EPR) effects and active targeting mediated by hyaluronic acid (HA) binding to glycoprotein CD44. The cargoes, including OST and L-Arginine (L-Arg), are released rapidly due to the degradation of GSH-responsive mesoporous organic silica (MOS). Then abundant reactive oxygen species (ROS) are produced from OST in the presence of high concentrations of NAD(P)H quinone oxidoreductase 1 (NQO1), resulting in the generation of NO and subsequently highly toxic peroxynitrite (ONOO) by catalyzing guanidine groups of L-Arg. These ROS, NO, and ONOO molecules have a direct impact on mitochondrial function by reducing mitochondrial membrane potential and inhibiting adenosine triphosphate (ATP) production, thereby promoting increased apoptosis and inhibiting metastasis. Overall, the results indicated that HMOA NPs has great potential as a promising alternative for the clinical treatment of cervical cancer.
癌症转移给当前的临床治疗带来了重大挑战。蛇床子素（OST）已显示出治疗宫颈癌和抑制转移的功效。尽管有这些积极成果，但其溶解度有限、口服吸收差、生物利用度低以及光敏感性阻碍了其临床应用。为了解决这一局限性，设计了一种谷胱甘肽（GSH）响应型纳米草药递送系统（HA/MOS@OST&L-Arg纳米颗粒，HMOA NPs），用于靶向递送OST并实现可级联激活的一氧化氮（NO）释放。HMOA NPs系统利用增强的渗透和滞留（EPR）效应以及透明质酸（HA）与糖蛋白CD44结合介导的主动靶向进行构建。由于GSH响应型介孔有机硅（MOS）的降解，包括OST和L-精氨酸（L-Arg）在内的货物迅速释放。然后，在高浓度的NAD(P)H醌氧化还原酶1（NQO1）存在下，OST产生大量活性氧（ROS），通过催化L-Arg的胍基生成NO，随后生成剧毒的过氧亚硝酸盐（ONOO）。这些ROS、NO和ONOO分子通过降低线粒体膜电位和抑制三磷酸腺苷（ATP）生成，直接影响线粒体功能，从而促进细胞凋亡增加并抑制转移。总体而言，结果表明HMOA NPs作为宫颈癌临床治疗的一种有前景的替代方案具有巨大潜力。
