基于生物正交反应激活的声动力学分子探针的设计与制备

Traditional phototherapies (including photodynamic therapy and photothermal therapy) have been found to be inadequate in the treatment of non-superficial tumors, which are severely restricted by the limited penetration of light. Considering that ultrasound can penetrate soft tissue above 10 cm, it will be an idea method to develop ultrasound as the excitation source of the sensitizer for sonodynamic therapy. However the sonosensitizers currently used for SDT are nanomaterials with complex structures, which results in the complexity of clinical research and the uncertainty on biosecurity. This project is to be designed and synthesized series of sonodynamic molecular probes which can be activated by bioorthogonal reactions. We will construct activatable sonodynamic probes based on small organic molecules. Take advantage of the characteristic of tumor microenvironment and tetrazine-based bioorthogonal reaction, the sonosensitizers will be activated in situ and utilized for killing tumor cells with high biotin receptor expression. We will perform the sonotoxicity evaluation of the synthesized sonosensitizers with 4T1 cells and the corresponding tumor mouse model, then screen out the sonosensitizers which are highly toxic to cancer cells for suppressing tumor growth and construct the activatable sonodynamic molecular probe system for targeting tumor microenvironments. This project will verify the high sonotoxicity of the targeting sonosensitizers, moreover provide a general strategy for the establishment of sonodynamic molecular probes.

由于受到光学穿透深度的限制，传统的光学治疗方法在应对非浅表性肿瘤的治疗时表现出明显的不足，而超声对于软组织的穿透深度可达10 cm，因此以超声作为敏化剂的激发源开展非浅表性肿瘤的声动力学治疗（SDT），将会极大的弥补目前非浅表性肿瘤的治疗缺陷。目前报道用于SDT的声敏剂均为结构复杂的纳米材料，这导致了临床研究的复杂性与生物安全的不确定性。本项目基于生物正交反应，设计合成激活式声动力学分子探针，即利用肿瘤微环境与生物正交反应在体内原位激活声敏剂的方式，构建有机小分子声动力学探针体系，并将得到的声敏剂用于杀死高表达生物素受体的肿瘤细胞。以上述探针先后对4T1细胞与相应的小鼠肿瘤模型进行声学毒性测试，从而筛选出敏化性能优良的声敏剂，建立针对肿瘤微环境的可激活策略的声动力学分子探针体系。研究结果既可以验证拟合成声敏剂的高效敏化性能，也为治疗非浅表性肿瘤高效声动力学分子探针创制提供新的策略。

由于受到光学穿透深度的限制，传统的光学治疗方法在应对非浅表性肿瘤的治疗时表现出明显的不足，而超声对于软组织的穿透深度可达10 cm，因此以超声作为敏化剂的激发源开展非浅表性肿瘤的声动力学治疗（SDT），将会极大的弥补目前非浅表性肿瘤的治疗缺陷。目前报道用于SDT的声敏剂多为结构复杂的无机纳米材料，这导致了临床研究的复杂性与生物安全的不确定性。鉴于此，本项目开发了一系列基于不同分子结构的有机声敏剂。在此基础上，通过AIE功能模块的引入以及相应纳米粒子的制备，显著地提高了有机声敏剂的敏化性能。结果表明，高效的声敏剂既可以是具有不同分子结构的新型敏化剂，也可以来源于已有声敏剂的分子组装优化。本项目为高效有机声敏剂的开发与应用提供了新的材料与选择，研究结果为治疗非浅表性肿瘤高效声动力学分子探针创制提供了新的参考。

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