基于生物相容性量子点可视化监测纳米胶束的肿瘤靶向及药物控释

The site-specific delivery and controlled release of drug is the key for exerting its function. As a promising carrier of oil-soluble anti-cancer drugs, the fabrication of nanomicelles is helpful for simutaneously realizing the tumor-targeted drug delivery and the controlled release of drug. Currently, there are many methods that can be used for these studies, for instance, in vitro testing techniques-chromatography, optical spectrum, etc.; in vivo testing techniques-PET, magnetic resonance imaging, CT imaging, etc. Although these techniques have been used widely, and a lot of achievements have been obtained, they still have some shortcomings: in vitro testing techniques are time-consuming, laborious and expensive, and they are hard to acquire "what was actually happening in living tissues"; the main shortcoming for in vivo testing techniques is expensive. Hence, the combination of in vitro and in vivo imaging techniques is very important for the study of the site-specific delivery and controlled release of drug. However, among the existing imaging methods, only the optical technique can be simutaneously applied to in vitro and in vivo research. Therefore, in this project, based on our previous studies, by using quantum dots with different photoluminesce colors and good biocompatibility as fluorescence probes, and combining visible light in vitro microscopy imaging and near-infrared light in vivo biomedical imaging techniques, we study further the visual imaging of the tumor-targeted delivery of nanomicelles and the controlled release of drug. This technique will be helpful to break through the restrictions of traditional methods, and can correspondingly improve research efficiency of drug.

药物的靶向传输和控制释放是药物发挥功效的关键。纳米胶束作为一种有前景的药物载体，可以帮助同时实现脂溶性抗癌药物的肿瘤靶向传输和控制释放。当前，药物靶向传输和控释研究手段主要有--离体检测技术如色谱和光谱；活体检测技术如PET、核磁共振和CT成像等。尽管这些技术的应用已取得了相当的成果，但不足之处也逐渐显现：离体检测技术耗时、耗力和耗钱，不易反映活体内真实情况；活体检测技术则是研究费用昂贵。因此，离体和活体技术的结合对研究靶向传输和药物控释十分重要。而在各种研究方法中，只有光学技术可同时应用于这两方面研究。为此，本项目拟在现有研究基础上，以不同荧光发射且生物相容性好的量子点作为探针，将可见光显微离体和近红外光生物活体成像技术相结合，可视化监测纳米胶束对肿瘤的靶向行为，并依此进一步探索对药物控释的相关光学监控。项目的顺利实施将有助于突破传统药学方法的限制，提高功能纳米胶束药物载体的研发效率。

肿瘤的离体、活体光学显像，以及基于显像的药物设计与疗效评估具有重要的科学意义。在这个国家自然科学基金的资助下，我们在油溶性生物相容性量子点的制备，两亲性高分子/油溶性量子点自组装的水相转移策略，和量子点探针在细胞和小鼠水平的光学成像，以及基于量子点的药物递送系统等领域都取得了一系列成果。.具体成果包括以下几个方面：1）制备了高质量的油溶性ZnAgInSe、AgInSe2/ZnS和ZnCuInSe/ZnS等量子点，其荧光发射波长在~470–800 nm可调，并探索了它们在生物医学成像中的应用；2）合成了油溶性的双发射InP/ZnSe/ZnS荧光量子点（即包括可见光波段的激子发射和近红外波段的缺陷发射），荧光发射波长~550–~1100 nm，探索了它们的水相转移以及在生物医学成像中的应用；3）利用咪唑基团修饰的高分子对油溶性ZnAgInSe/ZnS量子点进行表面水溶性改性，使得高分子覆盖的亚稳的ZAISe/ZnS量子点复合物发生可控的二次组装，提高QDs-Clusters探针的肿瘤被动靶向性；4）利用生物相容两亲性碳量子点（carbon dots, CDs）和药物（多柔比星）自组装构建水溶性药物载体，探索肿瘤治疗效果；5）制备了生物相容性更佳的水溶性ZnAgInSe、ZnAgInS等量子点，其荧光波长在~460–~760 nm可调，并成功用于生物医学成像；探索了无膦法合成油溶性CdTe量子点，摒弃了传统方法中的三正辛基膦等试剂，有利于CdTe量子点的“绿色”、大量制备；通过对发卡DNA序列的生物信息学优化，探索了基于纳米金的分子信标在mRNA（如STAT5b mRNA）检测中的应用。.基于这些研究成果，我们发表了12篇SCI检索的科研论文，并申请3项国家发明专利（已公开），培养了多名优秀的博士、硕士和本科毕业生。