基于SERS核的洋葱状纳米微结构药物载体的构建及其在肿瘤诊断治疗一体化中的应用基础研究

Theranostic is a novel promising therapy strategy, where diagnosis is combined with therapy through imaging of the tumor and realeasing drugs in the tumor position at the same time. It is of highly importance in the theranostic field to develop multifunctional drug carriers, which combine imaging, controllable release of drugs and targeting. In this work, novel onion-like drug carriers based on metal, mesoporous silica and liposome are proposed to locate the tumor position through SERS imaging, and to realize a controllable drug release through a pH sensitive liposome. The proposed carriers have the following salient advantages: (1) SERS signals are used for the tumor reginition to replace fluorescence signals by which a precise tumor recognition becomes posible because the fluoresence signals may be easily interferenced by autofluorence of the biological molecules. (2) The use of mesoporous silica/liposome core-shell structure as the drug carrier may enlarge the drug load, enhance the structral stability as well as the flexibility of the functional degign for controllable release of drugs. We will investigate the design, preparation of the onion-like drug carriers, imaging and reginition of tumor cells, and controllale release of drugs. The proposed work will provide a novel strategy to fabricate carriers for the theranostic application, which will be useful for a highly effective personalized cancer therapy.

作为一种新兴的治疗策略，肿瘤"诊断治疗一体化"是指利用成像手段对肿瘤进行定位，并同时实现对肿瘤部位的药物释放，从而通过一次用药达到同时诊断和治疗的目的。发展兼具成像、药物可控释放和靶向性的多功能药物载体是该领域迫在眉睫的任务。本项目提出一类基于多肽修饰的金属/介孔硅/脂质体多层结构的洋葱状药物载体，利用SERS光谱作为肿瘤成像信号，同时通过pH敏感脂质体实现药物的可控释放。它具有以下优势：（1）利用SERS光谱作为肿瘤成像信号，避免了荧光成像易受生物分子自发荧光干扰等缺点，可显著提高肿瘤定位的准确性。（2）利用介孔硅/脂质体核壳结构作为载药单元，可提高药物载体的容量和结构稳定性，同时对药物释放功能的设计也更加灵活。项目研究内容包括洋葱状药物载体的设计制备，肿瘤细胞成像及靶向性研究，以及药物可控释放。该项研究为"诊断治疗一体化"药物载体的构建提供了新思路，对实现高效的个体化治疗具有重要意义。

主要工作包括：（1）以SERS为核的洋葱状药物载体的设计与制备；（2）对肿瘤细胞的靶向性及成像研究；（3）药物在细胞内的可控释放三个方面。项目主要成果包括：（1）构建了一系列基于不同纳米材料的具有SERS核的洋葱状纳米结构药物载体，包括基于硅基纳米材料（介孔硅球，介孔硅棒），碳基纳米材料（碳纳米管，石墨烯），磁性纳米材料（超顺磁性氧化铁纳米粒子）和脂类纳米材料。实验结果表明该类药物载体信号稳定性好、药物携载容量大，对肿瘤识别的准确性和灵敏性高，可同时实现肿瘤定位及药物可控释放，在肿瘤“诊断治疗一体化”中具有潜在应用价值；（2）发展了荧光-SERS双模式成像示踪及光谱技术，结合SERS编码技术可同时对细胞内多种药物分子及载体进行示踪，并实现细胞内药物释放的动态过程监控和药物浓度检测等功能。（3）发表论文32篇（标注32篇）,SCI收录28篇（标注28篇），影响因子>3.0的24篇（标注24篇）。申请发明专利11项，授权5项；（4）参加国际会议并作邀请报告5次，口头报告36篇次；（5）培养博士生5名，硕士生15名。