基于乙二胺四乙酸插层锌铝双金属氢氧化物的晚期肿瘤抗转移免疫治疗研究  

Anti-metastatic Immunotherapy of Advanced Tumors Based on EDTA Intercalated Zinc-aluminum Layered Double Hydroxide

作　　者：李世奇 鲍群群 胡萍 施剑林[1,2] LI Shiqi;BAO Qunqun;HU Ping;SHI Jianlin(State Key Laboratory of High Performance Ceramics and Superfine Microstructures,Shanghai Institute of Ceramics,Chinese Academy of Sciences,Shanghai 200050,China;Center of Materials Science and Optoelectronics Engineering,University of Chinese Academy of Sciences,Beijing 100049,China;Shanghai Tenth People’s Hospital,Medical School of Tongji University,Shanghai 200435,China)

机构地区：[1]中国科学院上海硅酸盐研究所,高性能陶瓷和超微结构国家重点实验室,上海200050 [2]中国科学院大学材料科学与光电工程中心,北京100049 [3]同济大学附属第十人民医院,上海200435

出　　处：《无机材料学报》2024年第9期1044-1052,I0001,共10页Journal of Inorganic Materials

基　　金：国家重点研发计划(2022YFB3804500);国家自然科学基金(22322509,52072394,22335006);上海市优秀学科带头人计划(23XD1424200);上海市科委基础研究项目(23DX1900200);中国科学院前沿科学重点计划(ZDBSLYSLH029);上海市青年科技英才扬帆计划(22YF1433400)。

摘　　要：癌细胞的全身性转移是目前癌症晚期患者的主要死亡原因。由于肿瘤细胞的快速增殖和细胞外基质的异常沉积,晚期癌症大体积瘤体组织致密且刚度较高,这为晚期实体肿瘤的治疗带来了极大的困难。一方面,由于大体积肿瘤的结构特性,使得常规药物难以渗透至其内部,免疫细胞难以浸润;另一方面,硬基质上的肿瘤细胞具有更强的侵袭能力,这容易引起肿瘤的全身性转移。为了解决这一问题,本研究制备了乙二胺四乙酸(EDTA)插层锌铝双金属氢氧化物纳米材料(EDTA/LDH),基于两个平行的Ca^(2+)剥夺机制,开展了EDTA/LDH材料体系对晚期大体积实体瘤的抗转移免疫治疗研究。该材料在肿瘤微酸环境中,通过静电力作用贴附在肿瘤细胞膜上,并释放EDTA以螯合细胞连接蛋白中的Ca^(2+),切断部分细胞连接,从而降低大体积瘤体的致密程度,促进免疫细胞向瘤体内浸润。此外,该材料在机体内被巨噬细胞作为“异物”吞噬,引起钙库操纵性钙内流,激活巨噬细胞抗肿瘤免疫效应,抑制多形核髓系抑制性细胞(PMN-MDSCs)和调节性T细胞(Tregs)的促肿瘤侵袭作用。本研究将为晚期恶性实体瘤的抗转移治疗提供借鉴性思路和方法。Systemic metastasis of cancer cells is currently the main cause of death for patients with advanced cancer.Due to the rapid proliferation of tumor cells and abnormal deposition of extracellular matrix,the large-volume tumor tissue in advanced cancer is dense and stiff,which brings great difficulties to the treatment of advanced solid tumors:conventional drugs having difficulty in penetrating and immune cells facing challenges to infiltrate into their interior.Meanwhile,tumor cells on hard matrices have stronger invasive ability,which is prone to cause systemic metastasis of tumors.To solve this problem,this study prepared ethylenediaminetetraacetic acid(EDTA)intercalated zinc-aluminum layered double hydroxide nanomaterials(EDTA/LDH).Based on two parallel Ca^(2+)deprivation mechanism,the anti-metastasis immunotherapy of EDTA/LDH material system for advanced large-volume solid tumors was studied.In the slightly acidic tumor microenvironment,the material system adheres to the tumor cell membrane through electrostatic force,releases EDTA to chelate Ca^(2+)in cell adhesion proteins,cuts off part of the cell connections,reduces the stiffness of large tumors,and promotes the infiltration of immune cells into the tumor tissue.In addition,the material system is phagocytosed by macrophages as a"foreign body",causing calcium store-operated calcium influx,activating the anti-tumor immune effect of macrophages,and inhibiting the tumor-promoting invasion of polymorphonuclear myeloid-derived suppressor cells(PMN-MDSCs)and regulatory T cells(Tregs).This study will provide reference ideas and methods for the anti-metastasis treatment of advanced malignant solid tumors.

关 键 词：晚期癌症 免疫治疗 无机纳米材料 离子调控 

分 类 号：R318[医药卫生—生物医学工程] R730[医药卫生—基础医学]