磁光可控发热复合植入膜构建及在乳腺癌原位复发模型中的作用研究

The recurrence and metastasis of breast cancer induced by residual invasion after tumor resection has been regarded as the significant cause of poor prognosis for patients. As is known to all, the magnetophotothermal therapy can achieve a higher ablation temperature while applied in local region, hence, it can lead to fewer side effects than conventional treatments. We once prepared the PLGA magnetic microspheres to apply in HCC embolization hyperthermia, and we constructed a theranostics system through magnetic composite microbubble to investigate the ultrasound/magnetic resonance signals of tumor. However, how to take advantages from nanomaterials to construct a safe, effective implantable composite membrane with magneto-optic controlled heating property to solve the problem of postoperative recurrence of breast cancer, the issue has become the key scientific problem in this project. In our preliminary experiment, we creatively constructed a biodegradable, multifunctional and implantable composite membrane via near field direct writing electrospinning technology, the membrane that was loaded with Fe3O4 magnetic nanoparticles and black phosphorus quantum dots uniformly. In this project, the as-prepared membrane would be tested by a series of characterization, and then the biological safety after implanted in vivo would be investigated in terms of temperature rising, imaging properties and biology evaluation in vitro. Finally, the curative effect and the mechanism of action of this membrane-mediated magnetophotothermal therapy would be explore through vitro (breast cancer cells) and vivo (local recurrence model of mice) experiments. In summary, this project constructs an implantable membrane with the characteristics of dual mode heating and imaging, which will provide material support for the exploration of magnetophotothermal therapy, and to supply a new pattern for breast cancer postoperative treatment, as well as to afford the experimental basis while applied in other tumors’ treatment.

乳腺癌手术后残留浸润导致的复发和转移是患者预后不良的重要原因。磁光联合热疗可实现较高消融温度、可局部使用故全身副作用少。前期我们制备出用于肝癌栓塞热疗的PLGA磁微球及介导肿瘤超声/磁共振成像诊疗的磁性复合微泡。但如何利用纳米材料构建安全有效的磁光可控发热复合植入膜以用于防治乳腺癌术后复发，是本项目拟解决的关键科学问题。预实验中，我们大胆地通过近场直写电纺技术构建了均匀负载磁(Fe3O4 NPs)和光(黑磷量子点)热介质的可生物降解型多功能复合植入膜。本项目拟对其进行系列表征验证，而后通过体外升温及成像特性、生物学评价膜的体内植入安全性，进而观测磁光联合状态下植入膜对乳腺癌细胞和原位复发模型的疗效，最后对其作用机制进行研究。项目拟构建的兼具双模态发热和成像功能的纳米复合植入膜，将为磁光联合热疗提供新型介质，为乳腺癌术后综合治疗补充新的模式，亦为在其他肿瘤术后的局部植入应用提供实验依据。

乳腺癌手术后残留浸润导致的复发和转移是患者预后不良的重要原因。磁光联合热疗可实现较高消融温度、可局部使用故全身副作用少。但如何利用纳米材料构建安全有效的磁光可控发热载体以用于防治乳腺癌术后复发，是本项目拟解决的关键科学问题。在本项目中，我们创新性地通过先进的电纺技术构建一个均匀负载磁(Fe3O4 NPs)和光(黑磷量子点 BP QDs)热介质的高性能可控发热纳米复合植入膜。项目已对其进行系列表征验证，而后通过升温特性、生物学评估了膜的体内植入可行性及安全性。该植入膜的热性能展开了测试证实磁光热协同热效果要远优于同一条件下单一外场辐照效果。通过对静电纺丝制备膜过程的工艺进行优化及调控规律探索，该植入膜的热性能展开测试证实磁光热协同热效果要远优于同条件下单一外场辐照效果。对复合膜进行多次辐照仍具有持久的升温效应并保存稳定，且纳米磁及光热剂均匀分布无泄露，确保了其体内应用时具备良好的磁光协同热升温能力及升温持久性。通过 CCK8 法对人源乳腺癌细胞 MCF-7 以及正常乳腺细胞MCF-10A与膜共孵育后的急性毒性进行检测，结果表明在72 小时内膜对 MCF-7以及MCF-10A 细胞均没有产生细胞毒性。此外，相较于对照组植入膜的细胞增殖率出现随时间增加而上升的趋势，可归咎为复合植入膜能够模拟上皮表型细胞的粘附环境，通过降低细胞-基质间相互作用促进细胞-细胞相互作用从而提高增殖率。此外测定复合膜的溶血情况远优于国内外规定标准，有效规避了常规纳米热介质在体内使用时所面临的风险，体内植入的炎症亦证实其高度安全。进一步地，我们在细胞层面验证了植入膜的磁光联合热对乳腺癌细胞的协同热增强凋亡效应，并对相关基因表达与多条信号通路的相关性进行了研究，现正对其在活体层面的协同疗效展开探索。项目所构建的高性能双模态可控发热纳米复合植入膜，将为磁光联合热疗提供新型介质，为乳腺癌术后综合治疗补充新的模式，亦为在其他肿瘤术后的局部植入应用提供实验依据。