Regulation of Ion Homeostasis for Enhanced Tumor Radio-Immunotherapy.
Regulation of Ion Homeostasis for Enhanced Tumor Radio-Immunotherapy.
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离子稳态的调节用于增强肿瘤放射免疫治疗
DOI：
10.1002/advs.202304092
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发表时间：
2023-11
期刊：
影响因子：
15.1
通讯作者：
Deng, Haijun
中科院分区：
文献类型：
--
作者：
Qian, Rui;Yi, Xuan;Liu, Teng;Chen, Hua;Wang, Yuhong;Hu, Lin;Guo, Lingchuan;Yang, Kai;Deng, Haijun
细胞内/细胞外离子含量影响肿瘤细胞的生长和转移，以及各种抗肿瘤治疗的疗效。本文将碳酸酐酶抑制剂（CAI）装载到pH响应的碳酸钙（CaCO3）纳米颗粒上，然后用脂质体修饰这些纳米颗粒，以获得生物相容性的CaCO3/CAI@Lipsome (CCL)，以增强肿瘤放射免疫治疗。CCL可在肿瘤微环境中特异性分解，释放钙离子（Ca2+）和CAI，并使细胞外液pH值升高。CAI抑制肿瘤细胞内外氢离子（H+）的流动，使肿瘤酸性微环境发生逆转，细胞内H+升高，从而提高肿瘤对放疗的敏感性。之后，细胞内H+升高加上放疗引起的活性氧促进钙内流，导致细胞钙超载。此外，CCL定制含量的H+和Ca2+增强放疗诱导的免疫原性细胞死亡和树突状细胞成熟，增强全身抗肿瘤适应性免疫。同时，由于肿瘤酸性微环境的中和和Ca2+含量的增加，在X射线照射下，CCL治疗的肿瘤中的巨噬细胞从促肿瘤的M2极化到抗肿瘤的M1。因此，通过简单的纳米制备多向调节肿瘤细胞内/外pH/钙将为提高放射免疫治疗的疗效提供有力的途径。碳酸酐酶抑制剂负载和pH响应碳酸钙（CaCO3）纳米颗粒被设计用于调节肿瘤细胞内/细胞外的pH和钙离子。纳米颗粒提高了放疗的疗效，增强了放疗诱导的体外效应，对原发肿瘤和远处肿瘤具有良好的抑制作用。
Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase inhibitor (CAI) is loaded onto pH‐responsive calcium carbonate (CaCO3) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO3/CAI@Lipsome (CCL) for enhance tumor radio‐immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca2+) and CAI, as well as increasing the pH value of extracellular fluid. CAI restrains the flow of hydrogen ion (H+) inside and outside the tumor cells, resulting in the reversal of tumor acidic microenvironment and the increase of intracellular H+, both of which can improve the sensitivity of tumor to radiotherapy. Afterward, the increased intracellular H+ together with radiotherapy‐causes reactive oxygen species promotes calcium influx, leading to cellular calcium overload. Moreover, the CCL‐tailored content of H+ and Ca2+ strengthens radiotherapy‐induced immunogenic cell death and dendritic cell maturation, amplifying systemic anti‐tumor adaptive immunity. Meanwhile, macrophages in the CCL‐treated tumors are polarized from pro‐tumor M2 to anti‐tumor M1 under X‐ray exposure, owing to the neutralization of tumor acidic microenvironment and enhances Ca2+ content. Therefore, multi‐directional regulation of the intra/extra tumor cell pH/calcium by simple nano‐preparation would provide a powerful way to improve the efficacy of radio‐immunotherapy. Carbonic anhydrase inhibitor‐loaded and pH‐responsive calcium carbonate (CaCO3) nanoparticles are designed to regulate the pH and calcium ions in tumor cells intra/extracellularly. The nanoparticles improves the efficacy of radiotherapy and strengthen the radiotherapy‐induced abscopal effect, resulting in perfect inhibition of primary and distant tumors.
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