以光敏剂ALA作为自支撑材料的具有壳核结构的磁性胶体纳米晶体簇的构建及在膀胱癌靶向化疗中的应用

We have been researching about magnetic nanoparticles drug delivery system in the targeting chemotherapy for bladder cancer. We have constructed several types of magnetic nanoparticles drug delivery system for bladder cancer, such as CS-PAA, MWCNTs, and MCNCs, which have been used for chemotherapy. The above systems improved the effects of chemotherapy significantly, however, we have also found the non-specifity of these systems for targeting chemotherapy in their application. Therefore, it is the key point in this study that we should reform these magnetic nanoparticles drug delivery system to make them to be more specific targeting for bladder cancer. With the help of photosensitizer ALA absorbed by the tissue of bladder cancer specially and according to the concept of coordination ploymer, we have preliminaryly obtained MCNCs-ALA with core-shell structure by forming the shell on the surface of MCNCs through coordination ploymer of ALA and Zn2+. Based on our previous reseach, this study is designed to attempt to load chemotherapy drugs on the MCNCs templates, to build a novel type of magnetic nanoparticles drug delivery system with the Drug-MCNCs-ALA structure, and to verify the effect of targeting chemotherapy for bladder cancer by experiments in vivo and in vitro. We will design a novel type of magnetic nanoparticles drug delivery system with independent intellectual property rights, which could improve the specity of targeting chemotherapy for bladder cancer, and has extremely important value for clinical transformation.

我们课题组一直致力于磁性纳米载药系统在膀胱癌靶向化疗中的研究。我们构建了CS-PAA、MWCNTs及MCNCs等多种磁性纳米载药系统并应用于膀胱癌的化疗。上述材料明显提高了膀胱癌的化疗效果，但在应用中我们发现上述材料的靶向性不具有特异性。因此改进这些纳米材料，使其对膀胱癌具有更强的靶向性成为本课题的研究重点。我们借助光敏剂ALA可被膀胱癌组织特异性吸收的特性，利用配位聚合物的理念，已初步在MCNCs的表面通过ALA与Zn2+的配位聚合形成MCNCs的壳层，从而得到壳核结构的的MCNCs-ALA。本课题拟在前期基础上进一步尝试在MCNCs模板上负载化疗药物，形成Drug-MCNCs-ALA结构的新型磁性纳米载药系统，并通过体内外实验验证上述载药系统对膀胱癌靶向化疗的作用。通过本研究，我们将设计出一个具有自主知识产权的磁性纳米载药系统，提高了膀胱癌靶向化疗的特异性，具有重要的临床转化价值。

我们课题组一直致力于磁性纳米载药系统在膀胱癌靶向化疗中的研究。本项目成功构建以光敏剂ALA作为自支撑材料的具有壳核结构的磁性胶体纳米晶体簇于Fe3O4@ALA-ZnII结并将其应用于膀胱癌的治疗。 在Fe3O4@ALA-ZnII基础上，继续构建一种靶向纳米微泡gly/PED/RGD-PMAA Nbs作为药物运输载体准备用于膀胱癌的声动力治疗。此外在本项目研究过程中发现CX3CL1在人膀胱癌中异常表达并增了对CX3CL1的基础研究。Fe3O4@ALA-ZnII纳米载体通过反应条件的控制，实现不同厚度的 ALA配位聚合物壳层，因此也就可以得到可控的高负载量，我们研究中ALA的负载量达到17%；由于这种自支撑的壳层完全是由ALA 与金属离子构筑，因此使得载体表面获得高浓度的ALA 分布，将会极大提高载体的靶向性效果，将其初步将其应用于膀胱癌的光动力治疗中显著提高治疗效果。此载体具有自主知识产权，提高了膀胱癌靶向化疗的特异性，具有重要的临床转化价值。纳米微泡gly/PED/RGD-PMAA Nbs通过纳米微泡表面gly和PEG成分的修饰，使其对细胞的毒性作用明显降低，生物相容性较好，纳米微泡内填充有全氟乙烷（PFH），使其与微米级微泡相比同样能产生较强超声信号，具有较好的声学应用价值。该新型纳米微泡可以作为结构基础，进一步设计优化可与其它药物相结合，为临床肿瘤诊疗提供一个全新的平台。此外，我们以CX3CL1为研究对象开展系列体内外实验，表明CX3CL1在人膀胱癌中异常表达，其发生机制可能与通过调控RAF1、EIF4E、ETS1、CDH1基因蛋白表达，并影响ERK/MAPk通路与MYC上游调控因子，进而在膀胱癌中发挥作用。ERK/MAPK通路、MYC调控因子以及RAF1、EIF4E、ETS1、CDH1都与肿瘤的增殖、分化、凋亡、侵袭与迁移密切相关。因此CX3CL1基因有望成为治疗膀胱癌的一个新的靶点。