School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
College of Pharmacy, Jinan University, Guangzhou 510632, China.
Mater Sci Eng C Mater Biol Appl. 2021 Dec;131:112494. doi: 10.1016/j.msec.2021.112494. Epub 2021 Oct 18.
Cellular defense system represented by glutathione (GSH) greatly weakens the outcomes of cancer therapy by antioxidation and detoxification. GSH depletion has been proved to be an effective way to enhance the efficacy of reactive oxygen species (ROS)-based therapies and chemotherapy. However, the existing strategies of GSH depletion still face the problems of unclear biosafety and high complexity of multicomponent co-delivery. In this study, we developed a GSH-depleting carrier platform based on disulfide-bridged mesoporous organosilica nanoparticles (MONs) to destroy the cellular defense system for cancer therapy. Responding to the high level of GSH in cancer cells, the disulfide bonds in the framework of MONs could be broken and consumed substantial GSH at the same time. Moreover, this process also promoted the degradation of MONs. In order to evaluate the effect of this platform in cancer therapy, chemotherapeutic drug cisplatin was loaded into MONs (Pt@MONs) to treat drug-resistant non-small cell lung cancer. In vitro and in vivo results indicated that Pt@MONs efficiently triggered GSH depletion, promoted platinum-DNA adduct formation, and induced cell apoptosis, resulting in significant tumor growth inhibition without marked toxicity. Taken together, the cellular defense system-destroying nanoparticles provide a promising platform for enhanced cancer therapy.
细胞防御系统，由谷胱甘肽（GSH）代表，通过抗氧化和解毒作用极大地削弱了癌症治疗的效果。已证实 GSH 耗竭是增强基于活性氧（ROS）的治疗和化学疗法疗效的有效方法。然而，现有的 GSH 耗竭策略仍然面临着生物安全性不明确和多组分共递复杂性高的问题。在这项研究中，我们开发了一种基于二硫键桥联介孔有机硅纳米粒子（MONs）的 GSH 耗竭载体平台，以破坏细胞防御系统进行癌症治疗。针对癌细胞中高水平的 GSH，MONs 中的二硫键可以被破坏，并同时消耗大量的 GSH。此外，这个过程还促进了 MONs 的降解。为了评估该平台在癌症治疗中的效果，将化疗药物顺铂装载到 MONs 中（Pt@MONs）以治疗耐药性非小细胞肺癌。体外和体内结果表明，Pt@MONs 能够有效地触发 GSH 耗竭，促进铂-DNA 加合物的形成，并诱导细胞凋亡，从而显著抑制肿瘤生长，而没有明显的毒性。总之，破坏细胞防御系统的纳米颗粒为增强癌症治疗提供了一个有前途的平台。
