基于免疫激活与光热双功能的四氧化三铁纳米粒用于肿瘤治疗及其作用机制研究

Photothermal therapy (PTT) in cancer treatment has instant antitumor effect but might result in tumor residue leading to tumor recurrence, while macrophage-based antitumor immunotherapy has extensive systemic effect but with slow onset and limited therapeutic effect on solid tumors. We proposed a new antitumor strategy combining PTT with activation of macrophage-based immunotherapy. Iron oxide (Fe3O4) nanoparticles have good photothermal conversion properties. In pilot experiments, we found that after incubated with photothermal Fe3O4 nanoparticles prepared by our research group, the expression of the marker protein of M2 phenotype could be down regulated in macrophages cells, indicating that this nanomaterial has the potential to modulate macrophage phenotype transformation leading to immune activation and antitumor effect. However, the specific functions of Fe3O4 nanoparticles in the macrophage transformation process remain to be studied, and the mechanisms of this effect remain to be clarified. Thus, this project plans to construct novel Fe3O4 nanoparticles with dual functionalities of immune activation and photothermal effect. And its biological effects in macrophage transformation process will be studied in detail and its molecular mechanisms will be discussed. Clinically relevant breast cancer is chosen as tumor models to evaluate the combined antitumor activities and the anti-recurrence effect of the dual functional Fe3O4 nanoparticles in vivo and to study the mechanisms of this combined antitumor therapy.

针对肿瘤光热治疗起效快但易出现肿瘤残留及复发的局限性，以及基于巨噬细胞的肿瘤免疫治疗作用广泛但起效较慢且对实体瘤治疗作用有限的特点，提出光热联合激活巨噬细胞免疫的新型肿瘤治疗策略。四氧化三铁纳米粒具有良好的光热转化性能，在前期实验中本课题组发现所制备的光热四氧化三铁纳米粒与巨噬细胞共孵育后，可诱导其M2表型特征蛋白表达下调，预示该材料具备调节巨噬细胞转型从而激活免疫发挥抗肿瘤作用的潜力，然而其具体作用机制尚亟待阐明。本项目拟构建新型“免疫激活”“光热”双功能四氧化三铁纳米粒，在细胞水平对其调节巨噬细胞转型的生物效应进行系统评价，在分子水平对其作用机制进行阐释。选择热疗临床相关度较高且易耐药的乳腺癌作为肿瘤研究模型，在动物水平评价该新型双功能材料联合治疗肿瘤及抑制肿瘤复发转移的效果，并对其联合抗肿瘤机理进行深入探讨。

针对肿瘤光热治疗起效快但易出现肿瘤残留及复发的局限性，以及基于巨噬细胞的肿瘤免疫治疗作用广泛但起效较慢且对实体瘤治疗作用有限的特点，提出光热联合激活巨噬细胞免疫的新型肿瘤治疗策略。本项目构建新型 “免疫激活” “光热”双功能的四氧化三铁纳米粒，对其光热效应及对巨噬细胞转型的调控性能进行了系统研究，对其“免疫激活”“光热”双功能抗肿瘤疗效进行了评价，并对该双功能材料抗肿瘤机制及免疫调节过程中T细胞的作用进行了探索。.实验结果显示构建的四氧化三铁纳米簇（MNC）能有效诱导肿瘤微环境中普遍存在的肿瘤相关巨噬细胞亚型转换，从而降低肿瘤相关巨噬细胞的免疫抑制、增强巨噬细胞对肿瘤的杀伤作用。同时该材料具备光热转化能力，在激光激发下能够发挥光热效应进一步促进其免疫调节作用效果，上调肿瘤相关巨噬细胞的内吞、释放抗肿瘤细胞因子，募集T细胞进入肿瘤组织，增加肿瘤部位及血液中的T细胞分布，从而发挥抗肿瘤疗效并抑制肿瘤转移。.本研究结果揭示了光热效应对癌症治疗中免疫调节的积极影响，并提示了诸如四氧化三铁纳米粒的无机纳米光热转化材料，很可能具备光热促进的免疫调节效应，在肿瘤联合治疗等方向有着巨大潜力和应用前景。