具有可控发热特性的复合磁水凝胶在肿瘤术后治疗中的应用研究

Due to the nondeterminacy of the tumor margin, tumor often can’t be completely removed and the residual tumor cells would be the cause of recurrence or metastases. Base on this important issue, a novel magnetic composite hydrogel with anisotropic structure was fabricated by magnetic field assisted assembly, and was applied as implant material for tumor postoperative therapy. On one hand, the relationship between the iron oxide magnetic nanomaterial, hydrogel, applied magnetic field and the structures, the mechanism of controllable enhancement of heat induction are planned to investigate for further application in this project. In vitro tumor cell culture model is planned to be built on this composite which mimics the microenvironment of residual tumor cells in vivo and the efficiency of hyperthermia and synergy with chemotherapy against tumor cells cultured on this platform will be evaluated as a more reliable reference for in vivo studies. On the other hand, this magnetic composite hydrogel will be applied as postoperative implant material to eradicate residual tumor cells with magnetic induced hyperthermia and synergy with chemotherapy. This strategy in our project will inhibit the recurrence or metastases of tumor after surgery and provide a novel way for the application of magnetic induced hyperthermia in clinic.

由于肿瘤边界的模糊性，外科手术在切除实体肿瘤时常导致部分肿瘤细胞的残留，进而引起肿瘤的复发或转移。针对这一问题，本项目利用外加磁场辅助自组装的方法，制备了一种具有各向异性结构的复合磁水凝胶，作为植入材料开展肿瘤术后治疗。一方面研究铁氧体磁性纳米材料、水凝胶及外加辅助磁场的相关参数与复合材料结构和可控增强磁致发热特性的之间的关系及机制，实现其磁致发热能力的进一步优化;在此基础上利用复合材料模拟肿瘤细胞在体内的微环境构建细胞培养模型，结合复合磁水凝胶载药及控制释放功能，在体外评价研究该复合材料在肿瘤磁致热疗及热/化协同治疗中的优势，为体内研究提供更科学的参考。另一方面通过建立肿瘤动物模型，与外科手术结合将复合水凝胶作为术后植入/填充材料，针对残留的肿瘤细胞/组织开展磁致热疗或热/化协同治疗，降低肿瘤术后复发/转移率，为基于磁性纳米材料的磁致热疗在临床中的应用提供新思路。

外科手术在切除实体肿瘤时常导致部分肿瘤细胞的残留，进而引起肿瘤的复发或转移。针对这一问题，本项目在前期研究的基础上提出了利用蓝光固化法制备磁各向异性水凝胶，实现了对复合材料结构及磁各向异性的精细调控，提高了磁水凝胶的在静磁场、旋转磁场和交变磁场中的响应能力，制备优化后的磁各向异性水凝胶在交变磁场中的发热效率最高可达到对照磁各向同性水凝胶发热效率的300%，较此前报道的结果提高了150%，已完全能满足肿瘤磁热疗的需求。此外还提出利用外相相变原理制备磁各向异性水凝胶微球的新方法，其磁响应能力明显高于传统方法制备的磁水凝胶微球，该材料在磁热联合栓塞治疗肿瘤中具有良好的应用前景；同时利用复合材料模拟肿瘤细胞在体内的微环境构建细胞培养模型，经过优化制备条件后在复合材料上构建肿瘤多细胞球模型，评价由石墨烯柔性器件产生的特殊远红外新型肿瘤治疗方法在亚组织水平的热效应。活死细胞染色结果显示与不具备三维结构的二维培养模型相比，多细胞球模型显出明显更接近体内无血管期的肿瘤，显现出明显的尺寸梯度差异，在控制的环境温度下由石墨烯柔性器件产生的特殊远红外在多细胞球模型中显现出更强的穿透能力。该结果与后续裸鼠移植瘤模型和裸鼠转移瘤模型的结果相吻合，初步显示构建在复合磁水凝胶表面的肿瘤多细胞球模型在新型治疗手段和药物的体外评价方面具有作为动物模型补充的前景。