<br>双通道 Ca2+ 纳米调节剂通过内源性 Ca2+ 重新分布诱导细胞内 Ca2+ 紊乱以实现肿瘤放射增敏,Advanced Materials

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双通道 Ca2+ 纳米调节剂通过内源性 Ca2+ 重新分布诱导细胞内 Ca2+ 紊乱以实现肿瘤放射增敏
Advanced Materials ( IF 27.4 ) Pub Date : 2024-05-01 , DOI: 10.1002/adma.202401222
Dianyu Wang ₁ , Haixue Jia ₁ , Hongmei Cao ₁ , Xiaoxue Hou ₁ , Qian Wang ₁ , Jia Lin ₁ , Jinjian Liu ₁ , Lijun Yang ₁ , Jianfeng Liu ₁

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肿瘤细胞利用 Ca ²⁺来维持细胞稳态并承受各种治疗的外部压力。在此，构建了一种双通道Ca ²⁺纳米调节剂（CAP-P-NO），它可以通过肿瘤固有的Ca ²⁺的重新分布来诱导不可逆的细胞内Ca ²⁺紊乱，从而破坏细胞稳态，从而提高肿瘤的放射敏感性。在肿瘤过表达的酸和谷胱甘肽的刺激下，辣椒素和一氧化氮相继从CAP-P-NO中逸出，激活瞬时受体电位阳离子通道亚家族V成员1和兰尼碱受体，使细胞外Ca ²⁺流入并释放分别在内质网中的Ca ²⁺ 。肿瘤细胞中高水平的Ca ²⁺不仅会损害细胞器的功能，还会引起基因转录组的广泛变化，包括一组放射抗性相关基因的下调。将 CAP-P-NO 治疗与放射治疗相结合，可以显着抑制胰腺肿瘤和患者源性肝脏肿瘤，且副作用可以忽略不计。总之，该研究提供了一种通过内源性 Ca ²⁺再分配诱导肿瘤特异性细胞内 Ca ²⁺过载的可行方法，并证明了 Ca ²⁺紊乱治疗在增强肿瘤放疗敏感性方面的巨大潜力。

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A Dual-Channel Ca2+ Nanomodulator Induces Intracellular Ca2+ Disorders via Endogenous Ca2+ Redistribution for Tumor Radiosensitization

Tumor cells harness Ca²⁺ to maintain cellular homeostasis and withstand external stresses from various treatments. Here, a dual-channel Ca²⁺ nanomodulator (CAP-P-NO) is constructed that can induce irreversible intracellular Ca²⁺ disorders via the redistribution of tumor-inherent Ca²⁺ for disrupting cellular homeostasis and thus improving tumor radiosensitivity. Stimulated by tumor-overexpressed acid and glutathione, capsaicin and nitric oxide are successively escaped from CAP-P-NO to activate the transient receptor potential cation channel subfamily V member 1 and the ryanodine receptor for the influx of extracellular Ca²⁺ and the release of Ca²⁺ in the endoplasmic reticulum, respectively. The overwhelming level of Ca²⁺ in tumor cells not only impairs the function of organelles but also induces widespread changes in the gene transcriptome, including the downregulation of a set of radioresistance-associated genes. Combining CAP-P-NO treatment with radiotherapy achieves a significant suppression against both pancreatic and patient-derived hepatic tumors with negligible side effects. Together, the study provides a feasible approach for inducing tumor-specific intracellular Ca²⁺ overload via endogenous Ca²⁺ redistribution and demonstrates the great potential of Ca²⁺ disorder therapy in enhancing the sensitivity for tumor radiotherapy.

更新日期：2024-05-01

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