磷酸锰矿化肿瘤微球介导的免疫抗肿瘤效应研究

Inorganic biomaterials-based tumor immunotherapy has shown significant potential, while synergizing materials with immunogen to achieve tumor immunotherapy is still a great challenge. Manganese-based materials in which manganese ion (Mn2+) that can boost the innate immunity, indicating the outstanding potential for cancer immunotherapy of manganese-based biomaterials. In this study, we intend to prepare an immune-activating materials by manganese phosphate-based tumor spheroid mineralization, forming the materials-immunogen complexes (MnP-TS), to achieve the anti-tumor immune effect and reduce cytokine inflammation. MnP-TS with different material characteristics will be specially designed, and the correlation effects between the MnP-TS characteristics and immunologic function will be systematically studied in vitro and in vivo. In addition, the biodegradability and safety of manganese phosphate and MnP-TS, used as immune activating material, will be also evaluated. Furthermore, we will also investigate the immune cell regulation (T cell activation and macrophage polarization) by MnP-TS, and clarify the MnP-TS mediated tumor immunotherapy effect on tumor growth and metastasis. This study that preparing the manganese phosphate-spheroid complex materials for tumor immunotherapy by biomimetic mineralization, proposes a new strategy for immune-activating biomaterials study and further represents an alternative strategy for materials-driven tumor immunotherapy

无机生物材料在激活机体天然免疫并杀伤肿瘤方面具有重大潜在应用，二价锰离子近期被证实可激活细胞天然免疫抗病毒效应，据此我们初步推断含锰无机材料具有激活机体抗肿瘤免疫的作用。本项目拟采用仿生矿化方法制备磷酸锰-肿瘤微球复合材料（MnP-TS），研究其用作免疫激活材料介导的免疫抗肿瘤效应；结合体内外实验，系统研究磷酸锰-肿瘤微球制备的影响因素，评价分析材料的生物降解性和用作抗肿瘤免疫激活材料的安全性，阐明磷酸锰用作抗肿瘤免疫激活材料的可行性及其潜力，揭示MnP-TS对免疫细胞行为（T细胞活化和巨噬细胞极化）的调控作用机制，阐明MnP-TS介导的免疫抗肿瘤效应对肿瘤生长和转移的影响作用。项目研究制备的磷酸锰-肿瘤微球复合材料有望在肿瘤新型免疫治疗研究领域具有重大意义。

本项目基于仿生矿化方法研究磷酸锰矿化肿瘤组织及其介导的免疫效应，在肿瘤内原位矿化构建形成磷酸锰-肿瘤复合免疫位点，基于锰元素及矿化复合的作用，矿化肿瘤位点可有效激活机体抗肿瘤免疫效应，显著改善机体抗原递呈细胞（DC细胞）、巨噬细胞、T细胞和NK细胞等免疫细胞的抗肿瘤活化水平，并在诱导DC细胞成熟和M1型巨噬细极化方面作用显著。研究发现磷酸锰矿化肿瘤介导的免疫效应可显著促进肿瘤内杀伤性T细胞和NK细胞的活性和数量，能有效抑制小鼠肿瘤的生长且兼具良好的生物安全性。在此基础上，本项目继续研究了矿化磷酸锰对巨噬细胞免疫效应的调控作用，研究显示矿化磷酸锰可有效促进巨噬细胞M1型极化，同时发现磷酸锰可通过TGF-β1信号通路抑制胞外基质胶原蛋白分泌量，达到降低肿瘤组织基质密度的效果，对促进药物在肿瘤内渗透具有良好作用。此外，磷酸锰矿化复合材料在细胞调控及功能性材料制备及应用方面具有良好的拓展性和可控性。该研究为肿瘤新型免疫治疗技术、药物递送等领域研究提供重要基础，在抗肿瘤免疫医用材料研究方面具有良好的应用潜力。