Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, PR China; National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan, 430074, PR China; Hubei Bioinformatics and Molecular Imaging Key Laboratory, Huazhong University of Science and Technology, Wuhan, 430074, PR China.
Biomaterials. 2024 Dec;311:122673. doi: 10.1016/j.biomaterials.2024.122673. Epub 2024 Jun 17.
The adaptive antioxidant systems of tumor cells, predominantly glutathione (GSH) and thioredoxin (TRX) networks, severely impair photodynamic therapy (PDT) potency and anti-tumor immune responses. Here, a multistage redox homeostasis nanodisruptor (Phy@HES-IR), integrated by hydroxyethyl starch (HES)-new indocyanine green (IR820) conjugates with physcion (Phy), an inhibitor of the pentose phosphate pathway (PPP), is rationally designed to achieve PDT primed cancer immunotherapy. In this nanodisruptor, Phy effectively depletes intracellular GSH of tumor cells by inhibiting 6-phosphogluconate dehydrogenase (6PGD) activity. Concurrently, it is observed for the first time that the modified IR820-NH molecule not only exerts PDT action but also interferes with TRX antioxidant pathway by inhibiting thioredoxin oxidase (TRXR) activity. The simultaneous weakening of two major antioxidant pathways of tumor cells is favorable to maximize the PDT efficacy induced by HES-IR conjugates. By virtue of the excellent protecting ability of the plasma expander HES, Phy@HES-IR can remain stable in the blood circulation and efficiently enrich in the tumor region. Consequently, PDT and metabolic modulation synergistically induced immunogenic cell death, which not only suppressed primary tumors but also stimulated potent anti-tumor immunity to inhibit the growth of distant tumors in 4T1 tumor-bearing mice.
肿瘤细胞的适应性抗氧化系统，主要是谷胱甘肽 (GSH) 和硫氧还蛋白 (TRX) 网络，严重削弱了光动力疗法 (PDT) 的效力和抗肿瘤免疫反应。在这里，一种多阶段氧化还原稳态纳米破坏剂（Phy@HES-IR），由羟乙基淀粉（HES）-新型吲哚菁绿（IR820）缀合物与大黄素（Phy）组成，大黄素是戊糖磷酸途径（PPP）的抑制剂，被合理设计用于实现 PDT 引发的癌症免疫治疗。在这种纳米破坏剂中，Phy 通过抑制 6-磷酸葡萄糖酸脱氢酶（6PGD）活性有效地耗尽肿瘤细胞内的 GSH。同时，我们首次观察到，修饰后的 IR820-NH 分子不仅发挥 PDT 作用，还通过抑制硫氧还蛋白氧化酶（TRXR）活性干扰 TRX 抗氧化途径。同时削弱肿瘤细胞的两种主要抗氧化途径有利于最大限度地提高 HES-IR 缀合物诱导的 PDT 疗效。由于血浆扩张剂 HES 的出色保护能力，Phy@HES-IR 可以在血液循环中保持稳定，并有效地富集在肿瘤区域。因此，PDT 和代谢调节协同诱导免疫原性细胞死亡，不仅抑制了原发性肿瘤，而且刺激了强烈的抗肿瘤免疫反应，抑制了 4T1 荷瘤小鼠中远处肿瘤的生长。
Zotero 插件