近红外荧光增强型靶向纳米探针构建及细胞-药物作用可视化

Chemotherapy remains one of the most effective treatments for various cancers, and its efficiency crucially depends on the concentration of anticancer drugs in cancer cells and in normal cells. Real-time detecting the release and distribution of the active drug to realize the visualization of cell-drug interaction could be of great importance, especially in a non-invasive manner. Meanwhile, the drug-targeting property can reduce the side effects of chemotherapy. Therefore, in this project, we would like to fabricate a bifunctional probe with the function of targeted drug delivery and visualization of cell-drug interaction. Considering that the advantages of latent fluorophores, such as higher image resolution and lower signal background, and the properties of light-responsive nanoparticle, such as the controlled release of drug and convenient functionality on its outer surface, we would like to integrate their respective advantages to fabricate a turn-on near-infrared fluorescent targeted nanoprobe, in which, ligand-modified and light-responsive polymeric nanoparticles act as nanovectors, upconverting nanoparticles act as antennas to absorb NIR light and emit UV light locally, latent NIR fluorophore-modified prodrugs responsive to biomolecular stimulus are encapsulated inside the nanovectors. Analyzing the correlation between the intracellular fluorescence and cell viability as means, we would like to investigate the application of this novel nanoprobe in visualization of cell-drug interaction. In this way, the method of fabricating novel nanoprobe, the new ways and techniques to visualize cell-drug interaction are explored and investigated.

化疗是癌症治疗的主要支柱之一，其疗效取决于抗癌药物在癌细胞和正常细胞之间的浓度分布。以非侵入方式实时探测药物释放与分布，实现细胞与药物作用的可视化，显得尤为重要。同时，药物具有靶向性，可以减少毒副作用。因此，本项目拟构建兼具药物靶向传递和细胞与药物作用可视化功能的探针。考虑到潜荧光素具有高的成像分辨率和低的信号背景等优点，以及光敏纳米颗粒具有药物可控释放及其表面易功能化的特点，本项目拟将两者有机结合，以配体修饰的光敏高分子纳米颗粒为载体，以吸收近红外光而发射紫外光的上转换纳米粒子为天线，将可响应细胞内生物分子刺激的潜近红外荧光素修饰前药包埋在纳米载体内核，构建近红外荧光增强型靶向纳米探针。以分析细胞内荧光与细胞活性关系为手段，研究该探针在细胞与药物作用可视化方面的应用。籍此，对新纳米探针构建的方法，以及细胞与药物作用可视化的新方法、新技术进行探索和研究。

近红外荧光不仅对人体组织具有强的穿透力，同时也可避免组织自发荧光的干扰，尤其适宜细胞内非侵入的可视化成像。本项目旨在设计并合成一系列性能优良的近红外荧光分子。项目研究期间，我们合成一种水溶性近红外荧光分子和一系列具有大斯托克斯位移的荧光分子，并试验了其刺激响应性能。研究发现: (a) 可炔基修饰的基于二氰基亚甲基苯并吡喃的近红外荧光素，可用于氟离子的检测；但实验结果表明，该荧光分子，类似于其他的具有大共轭体系的荧光分子，具有聚集态荧光淬灭和斯托克斯位移较小的特点（容易导致自吸收的发生），不太适合于制备荧光纳米颗粒。(b) 基于激发态质子转移机理的荧光素，具有聚集态荧光增强和大斯托克斯位移的特点，相对来说，更适合于高性能荧光纳米颗粒的制备。目前为止，我们合成了一系列具有大斯托克斯位移的荧光分子，并研究了取代基电子效应、位置效应及位阻效应对荧光性能的影响，以探索产生近红外荧光的分子结构特点。这为进一步设计固态高荧光量子产率的荧光分子及近红外荧光成像奠定了理论及实验基础。