“多合一”分子探针靶向血栓多模态成像及药物-相变法高效溶栓的基础研究

Thrombotic diseases are a serious threat to human health. As soon as possible to diagnose thrombosis, rapid recovery of ischemic tissue reperfusion is the key to the diagnosis and treatment of thrombotic diseases. Combining the basis of previous research and the characteristics of materials, this project plans to construct a thrombotic molecular probe integrated with diagnosis and treatment. The polymer material PLGA is used as a carrier, and the third-generation thrombolytic drug tenepase is used as a probe targeting component and a thrombolytic drug. When it enters a blood vessel, it can specifically target thrombus fibrin to realize delivery probe and drug thrombolysis. Multi-modal imaging materials Bi2S3 and perfluorohexane (PFH) are used as cores to accurately diagnose thrombus by CT and photoacoustic imaging. At the same time, combining with low-intensity focused ultrasound (LIFU)-induced phase transition technology triggers liquid-gas phase change of PFH to achieve the "internal bombing" of the thrombus and promote probe infiltration and phase transition thrombolysis. The in vivo and in vitro experiments were carried out to verify its targeting and multimodal imaging effects. The thrombolytic effect and mechanism of a new high-efficiency thrombolysis method for drug-phase transition thrombolysis were studied. Multi-modal imaging was used to evaluate the thrombolytic process and effect in real time. We aim to develop a efficient, convenient, economical, and non-invasive "all-in-one" thrombus molecular probe that combines diagnosis and treatment to achieve rapid and accurate diagnosis and treatment of thrombosis.

血栓性疾病严重威胁着人类健康，在尽可能短的时间内确诊血栓并快速恢复缺血组织再灌注是诊治血栓性疾病的关键。结合前期研究基础及材料的特性，本项目拟构建诊疗一体化的的血栓分子探针。高分子材料PLGA为载体，第三代溶栓药物替奈普酶作为探针靶向组件及溶栓药物，当其进入血管后能特异性靶向血栓纤维蛋白实现递送探针及药物溶栓的功能；多模态成像材料Bi2S3和全氟己烷（PFH）作为内核，能实现CT及光声成像精准诊断血栓，同时，联合低强度聚焦超声（LIFU）致相变技术触发PFH发生液-气相变，实现血栓“内轰炸”，达到促进探针内渗和相变溶栓的目的。通过体内外实验验证其靶向性及多模态显影效果，研究药物-相变溶栓这种新型高效溶栓方式的溶栓效果及其溶栓机制，多模态成像实时评估溶栓进程及效果，以期研发一种高效、方便、经济、无创的兼具诊断和治疗的“多合一”血栓分子探针，实现血栓的快速精准诊疗。

血栓性疾病严重威胁着人类健康，本项目旨在通过构建功能丰富的纳米探针，研究对血栓的靶向递送性能，高效溶栓及调节血栓微环境，实现对血栓的诊疗一体化。为明确血栓靶向效果与血流速度的关系，我们构建了基于EWVDV短肽靶向p -选择素的血小板特异性纳米探针，结合相变材料全氟己烷和印度墨汁，实现了血栓的多模态成像，并在多模态成像的方式下进一步研究了不同血流流速对纳米探针靶向血栓的影响。为提高纳米探针的靶向递送能力，我们制备了具有LIFU响应的磁导航和主动靶向的仿生纳米系统，该仿生系统能在血栓部位累积，降低网状内皮系统吞噬，是递送溶栓药物的优良工具。为实现血栓的高效溶解，我们设计了一种靶向血栓纤维蛋白的相变型纳米探针，其中以PFH和溶栓药物rtPA为核心，CREKA多肽偶联在PLGA 纳米粒的外壳上。在LIFU照射下进行了纳米探针的相变表征和超声成像。进一步探讨了LIFU响应的药物体外释放情况；在PFH和rtPA的协同作用下，证实了纳米探针在体内外的高效溶栓能力。为持续清除异常升高的ROS，调节血管微环境，减少血栓部位的炎症因子，我们利用普鲁士蓝构建纳米探针，探讨了光致相变在血栓治疗中作用，证明了热消融诱导的纤维蛋白网络结构损伤的溶栓机制，并通过普鲁士蓝清除活性氧，实现了血栓诊断到治疗的综合管理，促进血栓诊疗技术的发展。