Abstract：
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.
摘要：
癌症转移对当前的临床治疗提出了重大挑战。蛇床子素（OST）已显示出治疗宫颈癌和抑制转移的功效。尽管取得了这些积极成果,其有限的溶解度，口服吸收不良，低生物利用度，光敏感性阻碍了其临床应用。为了解决这个限制，谷胱甘肽(GSH)响应的纳米草药递送系统(HA/MOS@OST&L-Arg纳米颗粒，HMOANP）被设计用于靶向递送具有可级联激活的一氧化氮（NO）释放的OST。利用增强的通透性和保留(EPR)效应和由结合糖蛋白CD44的透明质酸(HA)介导的主动靶向来工程化HMOANP系统。货物，包括OST和L-精氨酸（L-Arg），由于GSH响应的介孔有机二氧化硅（MOS）的降解而迅速释放。然后在高浓度的NAD（P）H醌氧化还原酶1（NQO1）的存在下，从OST产生丰富的活性氧（ROS），通过催化L-Arg的胍基产生NO和随后的高毒性过氧亚硝酸盐（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）的产生直接影响线粒体功能，从而促进细胞凋亡增加和抑制转移。总的来说,结果表明，HMOANPs作为临床治疗宫颈癌的一种有希望的替代药物具有巨大的潜力。
