NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan 523018, China.
J Control Release. 2024 Aug;372:386-402. doi: 10.1016/j.jconrel.2024.06.053. Epub 2024 Jun 25.
Ferroptosis-related tumor therapy based on nanomedicines has recently gained significant attention. However, the therapeutic performance is still hindered by the tumor's physical barriers such as the fibrotic tumor matrix and elevated interstitial fluid pressure, as well as chemical barriers like glutathione (GSH) overabundance. These physicochemical barriers impede the bioavailability of nanomedicines and compromise the therapeutic efficacy of lipid reactive oxygen species (ROS). Thus, this study pioneers a manganese-mediated overcoming of physicochemical barriers in the tumor microenvironment using organosilica-based nanomedicine (MMONs), which bolsters the synergy of photothermal-ferroptosis treatment. The MMONs display commendable proficiency in overcoming tumor physical barriers, due to their MnO-mediated shape-morphing and softness-transformation ability, which facilitates augmented cellular internalization, enhanced tumor accumulation, and superior drug penetration. Also, the MMONs possess excellent capability in chemical barrier overcoming, including MnO-mediated dual GSH clearance and enhanced ROS generation, which facilitates ferroptosis and heat shock protein inhibition. Notably, the resulting integration of physical and chemical barrier overcoming leads to amplified photothermal-ferroptosis synergistic tumor therapy both in vitro and in vivo. Accordingly, the comparative proteomic analysis has identified promoted ferroptosis with a transient inhibitory response observed in the mitochondria. This research aims to improve treatment strategies to better fight the complex defenses of tumors.
基于纳米医学的铁死亡相关肿瘤治疗最近受到了广泛关注。然而，治疗效果仍然受到肿瘤物理屏障（如纤维化肿瘤基质和升高的间质液压力）和化学屏障（如谷胱甘肽（GSH）过剩）的限制。这些物理化学屏障阻碍了纳米药物的生物利用度，并降低了脂质活性氧（ROS）的治疗效果。因此，本研究利用基于有机硅的纳米医学（MMONs）开创了一种在肿瘤微环境中克服物理化学屏障的锰介导方法，增强了光热-铁死亡治疗的协同作用。MMONs 由于其 MnO 介导的形状变形和柔软性转化能力，表现出出色的克服肿瘤物理屏障的能力，这有助于增强细胞内化、增强肿瘤积累和改善药物渗透。此外，MMONs 还具有出色的克服化学屏障的能力，包括 MnO 介导的双重 GSH 清除和增强的 ROS 生成，这有助于铁死亡和热休克蛋白抑制。值得注意的是，物理和化学屏障克服的综合作用导致了体外和体内增强的光热-铁死亡协同肿瘤治疗。因此，比较蛋白质组学分析已经确定了促进铁死亡，同时观察到线粒体中存在短暂的抑制反应。本研究旨在改进治疗策略，以更好地对抗肿瘤的复杂防御。
