磁性温敏微凝胶载药体系的构建及其在膀胱癌热灌注化疗中的应用研究

Hyperthermic intravesical chemotherapy, with hyperthermia as adjunct to intravesical chemotherapy, is an effective treatment method for bladder cancer. However, the lack of appropriate heating approach has somehow limited the application of thermochemotherapy in the hyperthermic intravesical chemotherapy for bladder cancer. To solve this problem, the project is proposing an innovative idea to synthesize magnetic thermosensitive microgels and utilize them in the hyperthermic intravesical chemotherapy for bladder cancer. In this project, novel magenetic thermosensitive microgels are to be synthesized based on magnetic iron oxide nanoparticles and thermosensitive copolymers with emulsifier-free emulsion polymerization technique. The surface functional groups, particle size and morphologies, magnetic property and thermo-sensitivity of the microgel particles will be adjusted. Meanwhile, the relationship between the particle structure of the microgels with their magnetocaloric effect, drug load and release capacity and cytocompatibility will be studied. Furthermore, the optimized parameters for the intravesical instillation of mice bladder cancer is to obtained, such as the instillation time, instillation frequency, instillation amount and the power of alternating magnetic field. The successful implementation of this project, can fully integrate the advantages of magnetic targeting, magnetic hyperthermia and controlled drug release, and provides scientific basis for the establishment of novel hyperthermic intravesical chemotherapy technique.

膀胱热灌注化疗是有效治疗膀胱癌的热化疗技术，然而缺乏合适的加热方式使得这一热化疗技术的发展受到限制。为解决这一问题，本项目创新性地构筑磁性温敏微凝胶并将其应用于膀胱癌的热灌注化疗。项目拟采用无皂乳液聚合技术，基于四氧化三铁磁性纳米粒子和温度敏感性聚合物，制备新型磁性温敏微凝胶；对其表面功能基团、粒子形态大小、磁性能、温度敏感性等参数的进行调控；并研究其磁热效应、载药量、温敏性药物释放、细胞毒性等性能与微凝胶粒子结构之间的关系；进而通过调整小鼠膀胱癌热灌注化疗过程中的灌注时长、灌注周期、交变磁场强度、载药微凝胶的灌注量等，获取热灌注化疗的最佳参数。这一项目的成功实施，可充分结合磁靶向、磁热疗、药物控释的优势，为建立一种新型的膀胱癌热灌注化疗技术奠定科学基础。

本项目主要通过有机/无机杂化微凝胶粒子的设计，利用磁性纳米粒子与温度敏感性聚合物合成磁性温敏微凝胶，并开展其磁热疗和肿瘤化疗方面应用的研究。项目利用乳化分散法和无皂乳液聚合制备了以磁性氧化铁和氧化钆纳米粒子为核，温敏性聚合物为壳层的新型磁性温敏复合微凝胶粒子。通过微凝胶粒子的粒径形貌、化学组成和表面电荷等分析，优化了复合微凝胶粒子的制备方法和参数。所制备的磁性聚合物的磁感应升温效果显著，在肿瘤热疗过程中，从体温开始升温完全可以达到热疗41-47℃的温度范围，并可以通过调整其中磁性纳米粒子的含量来控制所能取得的磁感应升温能力。同时，通过微凝胶粒子粒径大小随温度的变化证实了其温度响应性；复合微凝胶粒子表现出良好的细胞相容性，并且在充分负载肿瘤化疗药物后，通过调节体系的温度，其复合微凝胶粒子的药物释放率可达到95%以上，对于肿瘤细胞的杀伤效率也显著提高，有着较好的肿瘤治疗效果。本项目的研究为肿瘤治疗提供了新型的载药体系，可实现磁感应热疗和温度响应药物控释化疗相结合，为包括膀胱癌在内的多种肿瘤的热化疗提供了技术基础。项目资助发表SCI论文2篇，中文学术论文1篇，申请中国发明专利1项；培养硕士研究生和博士研究生各1名；项目投入各项经费也基本按预算支出。..