靶向卵巢癌的诊疗一体化荧光探针的设计合成及性能研究

In recent years, the incidence and mortality rate of ovarian cancer have been constantly increased in China. Early diagnosis and timely treatment are crucial to increasing the survival rate of ovarian cancer patients. Theranostic probe, a new approach to treat cancer, is of great significance to the theranostics of ovarian cancer. However, current theranostic probes typically use recognition group of the tumor target as the linker to connect fluorescent dye with anti-tumor drug. Therefore, the tumor target must have the ability to break the linker, which greatly limits the application range of the theranostic probes. In order to solve this problem, this project aims to develop a series of novel theranostic probes. These probes utilize fluorescent drugs (cresyl violet) with both fluorescent property and anti-tumor activity as the theranostic bi-functional group, which can directly connect to the recognition groups. This new type of theranostic probe does not require the recognition group to be the linker, and expands the range of recognized tumor target, which provides a new framework for the development of theranostic probes. Based on this concept, the aim of this project is the synthesis of theranostic probes for ovarian cancer using D-galactose as the recognition group of beta galactosidase (a type of ovarian cancer target) to link to fluorescent drugs (cresyl violet) possessing theranostic function. Through the research on the theranostic properties of these probes at molecular, cellular, and animal levels, we can screen the targeting specificity of the theranostic probes and therapeutic efficiency to achieve the purpose of simultaneous diagnosis and treatment.

卵巢癌的发病率和死亡率在我国逐年上升，早期诊断和及时治疗是提高患者生存率的关键，诊疗一体化探针作为癌症精准治疗的新途径，对卵巢癌的诊疗具有重要意义。现有的诊疗探针是以肿瘤靶标的识别基团作为桥链结构，连接荧光染料和抗肿瘤药物，它要求肿瘤靶标必须具有断裂桥链的功能，因此极大限制诊疗探针对肿瘤靶标的适应范围。为解决上述难题，本项目以兼具荧光特性和抗肿瘤活性的荧光药物(如甲酚紫)作为双功能基团，可直接连接识别基团设计一类新型诊疗探针。该类诊疗探针无需要求识别基团为桥链，拓展诊疗探针对肿瘤靶标的应用范围，为诊疗探针的设计提供新方法。基于这种设计策略，以D-半乳糖作为卵巢癌靶标β-半乳糖苷酶的识别基团，连接具有诊疗功能的荧光药物(如甲酚紫)，设计合成靶向卵巢癌的新型诊疗探针。测试这类探针在分子、细胞及活体水平的诊疗性质，筛选靶向性好、成像和治疗效率高的诊疗探针，实现同步诊断和治疗的目的。

本项目拟筛选同时具有荧光特性和抗肿瘤活性的荧光药物，通过荧光药物与卵巢癌靶标蛋白（β-半乳糖苷酶和亮氨酸氨基肽酶）的识别基团（D-半乳糖和亮氨酸残基）相来连接，构建靶向卵巢的诊断和治疗一体化的荧光探针。通过对分子水平，细胞水平和活体水平的研究，探究荧光药物对肿瘤细胞诊断和治疗的作用，建立诊疗型荧光探针的新方法。同时，拓展了以光敏剂为主体的被动靶向肿瘤的诊疗一体化探针的工作。.本项目按照研究计划，完成了预期的研究内容，顺利实现了项目既定目标。.1）.通过文献调研和荧光染料的合理设计，筛选了一批兼具荧光特性和抗肿瘤活性的荧光药物，例如甲酚紫，2,7-萘啶衍生物，喜树碱，阿霉素等，为诊疗探针的合理设计奠定了理论基础。.2）.合理构建了基于半菁染料的靶向β-半乳糖苷酶的荧光探针，并成功用于活细胞和斑马鱼内源性β-半乳糖苷酶的检测和成像，该探针在细胞水平对卵巢癌细胞具有高度的选择性，体现了其卵巢癌临床诊断能力。.3）.合理构建基于阿霉素的靶向亮氨酸氨基肽酶的诊疗荧光探针，该探针能够实现癌细胞的特异性识别和同步治疗的目的。这种基于荧光药物的策略为设计新型，高效的诊疗型荧光探针提供了理论指导。.4）.拓展了基于卟啉衍生物的核磁共振成像和光动力治疗用于癌细胞的诊疗的新方法。该项目是对荧光探针诊疗功能的衍生工作，探讨并对比主动靶向和被动靶向的优劣，并尝试将主动靶向和被动靶向相结合探索更高效的诊疗探针，是设计结合主动靶向和被动靶向诊断探针的新策略。.