硫化氢激活型光动力诊疗试剂的构筑及应用研究

Accurate diagnosis and effecient treatment of cancer has always been an important research topic. Compared with traditional methods such as surgery, chemotherapy and radiotherapy, photodynamic therapy (PDT) has the advantages of non-invasive, no cumulative toxicity and low drug resistance. However, PDT still faces some serious challenges, such as low penetration, phototoxicity and oxygen-dependence . Based on the our research background and experience, we intends to develop hydrogen sulfide-activated PDT reagents for anti-tumor theranostics. First, photosensitizers having red/near-infrared light absorption and emission will be developed to achieve a large penetration depth. At the same time, the development of a type I PDT reagents with low oxygen dependence to overcome the limitations of traditional type II PDT reagent on the treatment of hypoxic tumors. Using the tumor marker hydrogen sulfide as an activating reagent,we will rationally select different hydrogen sulfide response mechanisms, and use PET, FRET and other strategies to design photosensitizer systems that show both fluorescence and ROS generation activation to achieve specific tumor diagnosis and treatment. The implementation of this project will help improve the accuracy of tumor diagnosis and the effectiveness of tumor treatment, while reducing toxic side effects, providing new methods and ideas for the clinical treatment of cancer.

癌症的准确诊断与治疗一直是研究人员十分关注的重要课题。相对于传统的手术、化疗和放疗手段，光动力治疗（PDT）具有非侵入性，无累积毒性，耐药性小等优势。但是，PDT仍然面临一些严峻的挑战，如穿透性小、光毒性以及对氧气依赖性等。基于目前PDT研究领域现状，结合自身的研究背景与基础，申请人拟展开硫化氢激活型PDT试剂的开发与抗肿瘤应用研究。首先，开发具有红光/近红外光吸收和发射的光敏剂以实现较大的穿透深度。同时，发展对氧气依赖度小的I型PDT试剂针以克服传统II型PDT试剂对乏氧肿瘤治疗限制。以肿瘤标志物硫化氢作为激活试剂，合理的选择不同的硫化氢响应机制，分别利用 PET、FRET等策略设计荧光及ROS同时激活的光敏剂体系，实现肿瘤的特异性诊断与治疗。本项目的实施有助于提高肿瘤诊断的准确性及肿瘤治疗的有效性，同时降低毒副作用，为癌症的临床治疗提供新的方法与思路。

光动力治疗PDT目前面临穿透性小、光毒性以及对氧气依赖性等问题，治疗效果及应该用范围有限。本项目开展了一系列针对性研究，以增大治疗深度、降低氧气依赖性提高肿瘤选择性等，实现肿瘤的特异性诊断与治疗。重要研究成果如下: 1) 通过亚细胞器靶向，原为产生活性氧破坏亚细胞器结构和功能，提高光动力治疗效果，分别构筑了分别靶向内质网、高尔基体、线粒体等光敏剂；2）发展了系列基于有机小分子和金属配合物的I型光敏剂，降低了氧气依赖性；3）通过铁死亡和凋亡协同作用，提高对具有凋亡抵抗的癌细胞的治疗潜力；4）开发肿瘤微环境激活型近红外光敏剂，既增加了穿透深度，还提高了肿瘤选择性，降低了毒副作用。相关研究成果发表于Nat. Commun., Angew. Chem. Int. Ed., Chem. Sci.等国际一流期刊，申请专利两项。

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