功能性磁性微纳机器人的构建与抗肿瘤应用研究

生物医用微纳机器人的理想特性应包括自主推进、精确控制、成像引导、 优异的生物相容性和生物降解性，并能够高效地装载和可控地释放功能性物 质，例如治疗药物、成像剂和生物传感分子。然而，将这些复杂的功能集成 到单个微纳机器人中仍然具有非常大的挑战。因此，为了最大化微纳机器人 的优势并加速其临床转化，优化微纳机器人的构建以满足靶向癌症的需求是 至关重要的。为此，本研究针对肿瘤靶向治疗应用的问题，基于纳米医学、 微纳制造、材料学等多学科交叉融合，设计了四种功能递进的磁性微纳机器 人，有望为提高微纳机器人的生物医用提供新思路。 基于最小模块的三珠磁性微型粒子机器人以及光热刺激响应治疗策略， 将具有近红外光响应功能的偶氮分子及肿瘤化疗药物阿霉素共价结合到三 珠微型机器人上。结果显示，磁性微米机器人浓度高达 200 µg/mL 时仍显示 出良好的细胞相容性。经过近红外光热辐照后，三珠微型机器人显示出快速 的 NIR 光热响应，4 分钟内温度迅速升温至 50℃。同时，负载到三珠微型机 器人表面的阿霉素在热的作用下被触发释放。在磁引导的哑铃型微流道运动 实验中，其可通过对 NIR 的响应，对癌细胞表现出光热及药物的靶向杀伤效 果。结果表明，这种三珠微型机器人具有良好的肺癌细胞靶向治疗的潜力。 采用光刻技术及磁控溅射技术高通量制备微型 L 形机器人，结合材料表 面的微纳结构对免疫细胞的极化作用，构建了具有良好生物相容性的纳米级 光滑表面的免疫 L 形微型机器人。利用静电相互作用将带正电荷的 DOX 负 载到微型机器人的表面上，DOX 表现出 pH 响应释放行为。在巨噬细胞与 L 形机器人的共同培养中发现，具有纳米光滑表面的机器人不仅具有良好的细 胞相容性，还能诱导巨噬细胞向抗肿瘤表型的 M1 型巨噬细胞极化。通过磁 引导，微型机器人能够靶向三维（3D）肿瘤球体并杀死癌细胞。结果表明， 这种微型机器人具有磁引导、激活巨噬细胞免疫治疗肿瘤功能和 pH 响应药 物释放功能，为肿瘤免疫靶向型的微型机器人提供了良好的思路。 进一步利用仿生 M1 表型巨噬细胞膜靶向免疫的概念，及利用具有光热、 光声性质的黑磷量子点，开发了 M1 巨噬细胞膜包被的磁性光热纳米机器人， 用于光声成像引导的肿瘤治疗。纳米机器人能够从原始巨噬细胞中继承功能 蛋白质并发挥靶向免疫抑制作用。其中，黑磷量子点和 DOX 也大大提高了ROS 的产生和化学光疗的效果。结果表明，此纳米机器人可作为多功能肿瘤 免疫靶向平台，用于调节肿瘤微环境，达到 PA 成像和磁引导下的协同治疗 效果。 最后，为了提高光热治疗的效果，选择具有更好光热性能的有机光热材 料聚吡咯作为光热光声组分，利用原位化学法合成聚吡咯/四氧化三铁纳米 复合物。同时，为了避免单一细胞膜的功能的不足，采取血小板膜/M1 巨噬 细胞膜双膜包裹构建仿生聚吡咯纳米机器人。结合化疗药物替莫唑胺的抗肿 瘤作用，磁性纳米机器人在小鼠原位胶质瘤模型中表现出光声介导的联合光 热抗肿瘤效果。

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