荧光和MRI双影像指导的肿瘤靶向的MOFs纳米光敏剂的光动治疗研究

Facing the challenge of the urgent need for high sensitivity image tracking and effective treatment of tumor tissue, this study intends to construct metal-organic framework (MOFs) photosensitizers with fluorescent imaging, magnetic resonance imaging, and high PDT effect. Then, the erythrocyte membrane is camouflaged to enhance blood circulation and tissue residence time in the body, and finally the aptamer targeting molecule is modified to achieve the high enrichment of the photosensitizers on tumor domain. First, the repulsive force between electrons is reduced by simultaneously introducing the donor-acceptor to achieve a smaller ΔEST of the AIE molecule, resulting in an AIE ligand molecule having a high yield of 1O2. The ligand molecule is then coordinated with Gd to form a MOFs photosensitizer. The MOFs structure limits the intramolecular spin-motion of AIE ligands, exposes more active sites, and promotes energy exchange between triplet T1 and molecular oxygen, and has the enhanced fluorescence emission and high yield of 1O2. The introduction of the Gd metal node produces a high relaxation rate, which brings the effect of magnetic resonance imaging. In addition, fluorescence imaging has high sensitivity and is capable of detecting very small tumor tissues. The advantage of MRI imaging is that it has high spatial resolution, and the combination of the two imaging methods has the dual advantages of high sensitivity and spatial resolution. The developed tumor-targeted MOFs nano photosensitizers could achieve high photodynamic therapy effect with guidance by fluorescence and MRI imaging. This study will form the basic rules for the developing of the high sensitive tumor imaging and high effective therapy.

面对肿瘤组织的高灵敏高分辨影像示踪及高效治疗的重大需求，本项目拟构建具有荧光示踪、磁共振成像、高效PDT的MOFs纳米光敏剂，以红细胞膜包覆伪装来增强血液循环和组织驻留时间，修饰适配体靶向分子来实现光敏剂在肿瘤部位的高富集。首先利用同时引入电子供体-受体的方法来化学修饰AIE分子，降低电子间排斥力使AIE分子具有较小ΔEST，获得高的单线态氧产率。再以这种AIE分子与钆配位形成MOFs光敏剂。MOFs结构限制了AIE配体的分子内自旋运动，又能暴露较多的活性位点，促进三线态与分子氧的能量交换，显著增强单线态氧产率，同时产生增强荧光，因高的敏感性能检测出极微小肿瘤。钆金属节点的引入，使MOFs光敏剂又具有高的弛豫率产生高空间分辨率的磁共振成像。本项目发展的荧光和MRI双影像指导的、肿瘤靶向的MOFs纳米光敏剂，可用于肿瘤的高效PDT，这将为灵敏的肿瘤成像和高效治疗提供理论依据和实验基础。

光动力疗法（PDT）是一种微创治疗方法，能够对局部病变进行选择性破坏，从而受到人们的广泛关注。光敏剂（PSs）是PDT的重要组成部分，可以将光能传递给氧气产生具有细胞毒性的活性氧（ROS），破坏细胞形态和功能，最终导致癌细胞损伤和凋亡。所以开发高效的PSs成为人们关注的焦点。金属-有机骨架（MOFs）的多孔性和高比表面积不仅使其在气体储存和分离、传感器和催化方面表现出优异的性能，而且在PDT治疗领域也表现出优异的性能。本项目主要采用液体扩散法设计并制备了氧化铁负载的金属-有机骨架（FeTCPP/Fe2O3 MOFs）纳米晶。铁金属节点的引入和Fe2O3的负载可以有效催化Fenton反应产生羟基自由基（•OH），并通过产生氧气来克服肿瘤组织的缺氧环境。卟啉光敏剂在MOFs结构中的单分散性和孔隙性能够暴露出更多的活性位点，促进卟啉分子与氧分子之间的能量交换，从而提高了光动力治疗效果。因此，产生的羟基自由基和单线态氧（1O2）可以协同作用于肿瘤细胞，达到增强肿瘤治疗效果的目的。然后，对MOFs材料进行红细胞膜包裹伪装，以增强该材料在体内组织和血液循环的驻留时间，最后对目标分子进行AS1411适配体修饰，实现MOFs光敏剂在肿瘤区域的高度富集。实验结果证实，被红细胞膜伪装的MOFs纳米材料可以有效降低副作用，提高PDT和化疗（CDT）的协同治疗效果。本研究不仅利用MOFs纳米材料从本质上提高了PDT和CDT的疗效，而且利用伪装方法进一步将FeTCPP/Fe2O3富集在肿瘤部位，达到了多重增益的目的。这些结果将为肿瘤靶向MOFs纳米材料的开发提供理论和实践指导。