光控释放非分泌型TNF-α的智能型巨噬细胞用于转移性结肠癌的治疗

Currently, there are no effective treatments for metastatic colon cancer. The specific enrichment of therapeutic factors in metastatic sites is thought to be an effective therapeutic strategy. Taking advantage of macrophages’ natural tumor-homing and strong phagocytosis capabilities, the project aims to develop a near-infrared irradiation (NIR) light-controlled functional and intelligent macrophage delivery vehicle for treating metastatic colon cancer. Macrophages will be engineered to highly express non-secreted TNF-α, and acquire a capability of triggering TNF-α by uptaking indocyanine green-sericin (ICG-S) nanoparticles with fluorescence and photothermal conversion characteristics. Once (ICG-S) nanoparticles loaded macrophages reach metastatic sites through tumor-homing, ICG-S nanoparticles respond to exogenous NIR generating heat to "blast" macrophages，resulting in the release of intracellular TNF-α, subsequently causing cancer cells death. We will optimize the preparation of this type of functional and intelligent macrophages, thoroughly evaluate the efficiency and safety of the macrophage-based treatment strategy in vitro and in vivo, in hope of providing a new strategy for metastatic cancer treatment.

转移性结肠癌是临床治疗难点。增强治疗因子在转移灶的特异性高效富集是杀伤肿瘤细胞有效策略。本项目拟利用巨噬细胞天然的肿瘤趋化性和强吞噬特性，将其改造为细胞载体，特异性靶向递送治疗因子至肿瘤转移灶，用于转移性结肠癌治疗。拟用基因工程技术改造巨噬细胞，使其高表达非分泌型TNF-α并负载上有荧光特性和光热转换效应的吲哚菁绿-丝胶纳米粒；这些纳米粒将作为非分泌型TNF-α的释放“开关”；当巨噬细胞主动趋化到肿瘤转移灶后，吲哚菁绿-丝胶纳米粒发射荧光暴露转移瘤，引导外源性近红外光精准照射转移部位；此时吲哚菁绿响应近红外光，产生热，“爆破”巨噬细胞，触发胞内TNF-α释放，强效杀死肿瘤细胞，由此构建出功能化、智能型巨噬细胞。本项目将研发该功能化、智能型巨噬细胞的最佳制备工艺，体内体外实验全面评估该治疗策略的有效性和生物安全性，为临床治疗转移性肿瘤提供新手段。

机体内某些细胞，如干细胞、巨噬细胞和T细胞，具有天然的肿瘤归巢能力，可作为药物载体，实现肿瘤药物的靶向递送，发挥抗肿瘤效应。然而，传统的基于基因工程化的细胞载体仅启动单模模式的治疗，且缺乏对治疗药物在肿瘤局部释放的精确时空控制，存在严重的全身毒性作用。本项目利用工程化编辑巨噬细胞，获得细胞内表达非分泌型EGFP-TNFα，且携带NIR响应性的光热纳米反应器的功能化巨噬细胞。该功能化巨噬细胞类似“特洛伊木马”方式靶向肿瘤组织，经近红外光照射产生光热治疗效应，同时光热效应导致巨噬细胞裂解释放效应蛋白，从而实现肿瘤组织时空可控的光热与生物联合治疗效应。因此，我们采用双工程化编辑巨噬细胞和近红外辐射作为外源性触发开关的策略，不仅实现了精确控制、时空随需的释放效应蛋白，而且代表了一种新的基于细胞的癌症治疗的双模态治疗方法。