多功能微纳气泡的构建及应用于医学诊疗一体化的研究

In recent years, the application of micro- or nano- platform as carriers for targeting and delivery of diagnostic and therapeutic agents has received growing interest. These “theranostic” platforms can be used to understand the occurrence, development, metastasis and treatment process of diseases, such as tumor and cardiovascular disease, etc. By the development of multifunctional micro- and nano-structured carriers incorporating both an imaging agent and therapeutic drug, it will be possible to merge the diagnostic aspect with the therapeutic aspect, which may be able to target the delivery of drugs and imaging probes to the site of diseas. The main aim of this project is to fabricate the theranostic multifunctional micro- and nano- bubbles by using the methods of assembly, chemical conjugation and magnetic or ultrasonic fields’ induction. The structure of bubbles includes the various biomedical nanoparticles, therapeutic agents and imaging contrast agents, etc, which must have optimized size, excellent stability and good theranostic characterization. Based on the novel theranostic composite bubbles, the multimodality imaging, including the ultrasound imaging, magnetic resonance imaging and optical imaging, can be applied within the same bubble device. At the same time, we can monitor the drug delivery effect and comprehensively understand the real state of the complicated biological in vivo state when carrying out the high resolution diagnostic imaging. The research will mainly focus on the selection of the shell materials and the multifunctional assembly of the multi-agents embedded into microbubbles’ platform. Moreover, the relationship between the structures and the functions, the stability of bubbles and biological effect will be studied in detail, especially for targeting efficiency. We hope this project can provide the novel theranostic platform to improve both imaging and drug delivery properties providing enhanced contrast in medical imaging by visualizing the location of malignant cells in the body and selectively target drugs to the tissues with minimal side effects.

设计和构建疾病靶向、诊断与治疗相结合的载体输运系统，用于肿瘤、心血管等重大疾病发生、发展、转移和治疗过程的研究，建立将临床诊断与治疗同时结合的治疗一体化新方法及技术，能为重大疾病的个体化诊疗提供新工具和新方法。本项目拟以智能载药微气泡结构的设计、构筑为核心，以气泡膜壳材料、厚度、粘弹特性、表面修饰或携载药物与结构稳定关系为基础，发展基于微气泡药物输运系统的超声、磁共振、光学等多种影像增强技术，并应用于高分辨图像实时监控与准确引导下药物治疗方案的建立，治疗效果的判定和预后评估。研究主要包括微气泡膜材、功能性纳米颗粒的设计与可控制备；利用组装、化学偶联、外场介入等微纳制造技术结合针对疾病靶点的分子探针和药物分子等功能组分制备医用诊疗一体化微气泡载体材料；载药微气泡结构的稳定性与生物学效应；以及针对靶向疾病诊疗一体化的体内外功能评价。通过研究，拟实施针对疾病靶点的集成主动和被动联合靶向策略，为无损伤检测疾病的发生、发展机制及有效治疗的研究提供崭新的技术平台，为相关后续的应用发展铺垫基础。

基于微纳米技术发展针对重大疾病诊疗的新方法、新材料及新药物，是疾病发生、发展及实时监控的重要方向之一。项目首先完成了新型微纳气泡的构建研究，包括微气泡表面磁性纳米颗粒和靶向蛋白分子的可控自组装、纳米级多层含气声敏感脂质体的构建、磁响应原位微气泡药物输运系统的构建；进而，完成了微纳气泡与细胞在声能操控下的药物递送和生物学效应，包括超声微气泡介导细胞基因转染、磁性纳米颗粒在肿瘤细胞内的递送以及氧化应激效应；最后，选择优化的微纳气泡结构，实现了小鼠体内病灶的高靶向和诊疗一体化应用研究。尤其基于构建的新型表面同时偶联超顺磁性纳米颗粒、肿瘤新生血管和肿瘤细胞坏死因子相关凋亡诱导配体蛋白（RGD-L-TRAIL）的磁性微气泡分子探针；和装载治疗性硫化氢气体前体药物茴三硫和磁性纳米颗粒的瘤内微环境智能响应原位产生气体的纳米脂质体复合结构。在动物水平实现了肿瘤的高靶向效率，超声/磁共振双模态影像监控下的更良好的肿瘤治疗一体化取得突破性进展。. 通过四年的项目执行，根据项目主要研究内容和研究目标，顺利完成了整体计划任务：（1）共发表标注基金项目号的学术论文16篇，其中SCI论文13篇，合计影响因子88.225，其中包括ACS Nano(SCI, IF=13.942)，Advanced Functional Materials(SCI, IF=12.124)，Theranostics(SCI, IF=8.766)，Journal of Controlled Release(SCI, IF=7.786)等杂志在内影响因子大于5的论文7篇；中文核心期刊论文1篇；会议论文全文1篇；申请专利3项；参编英文专著1部。（2）2014年，荣获江苏省医学科技三等奖（排2）。（3）项目负责人获2017年东南大学仲英青年学者，2017年第十四批“六大人才高峰”高层次人才项目（C类）。（4）受邀参加国际国内学术会议15次，其中国外国际会议2次；做大会邀请报告1次，分会邀请报告4次；并受邀参加了香山科学会议第614次“生物医学影像发展战略”学术研讨会。（5）积极开展国内外学术合作交流，邀请国内外知名学者到实验室访问、做学术报告共4场；与美国University of California, Davis，南京鼓楼医院和中大医院开展合作研究共合作发表SCI论文3篇。