Abstract：
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-NH2 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.
摘要：
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，严重损害光动力疗法（PDT）的效力和抗肿瘤免疫反应。这里,多级氧化还原稳态纳米破坏剂(Phy@HES-IR)，由羟乙基淀粉（HES）-新吲哚菁绿（IR820）缀合物与physcon（Phy）整合，戊糖磷酸途径（PPP）的抑制剂，合理设计以实现PDT引发的癌症免疫疗法。在这个纳米分裂器中，Phy通过抑制6-磷酸葡萄糖酸脱氢酶（6PGD）活性有效地消耗肿瘤细胞的细胞内GSH。同时,首次观察到修饰的IR820-NH2分子不仅发挥PDT作用，而且通过抑制硫氧还蛋白氧化酶（TRXR）活性来干扰TRX抗氧化途径。肿瘤细胞的两种主要抗氧化剂途径的同时弱化有利于最大化由HES-IR缀合物诱导的PDT功效。凭借等离子体膨胀器HES的优异保护能力，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，它不仅抑制了原发性肿瘤，而且刺激了有效的抗肿瘤免疫力，以抑制4T1荷瘤小鼠中远处肿瘤的生长。
