基于裂开型核酸适配体-核苷衍生物自组装体的肿瘤诊疗探针构建及应用研究

The design and synthesis of simple, flexible, highly specific and highly effective probes for tumor theranostics are of great significance in the research of cancer detection and treatment. In this project, a new type of aptamer functionalized self-assemblies probe for tumor theranostic is constructed by using tumor activated split aptamer and nucleoside derivatives self-assembled nanoparticles. A split aptamer probe specificly targeting liver cancer will be designed to construct a tumor activation molecular probe with multiple signal patterns such as fluorescence “off” to “on” or fluorescence energy resonance transfer; multifunctional self-assembled nanoparticles with tumor treatment and base recognition capability will be constructed by synthesizing hydrophilic-hydrophobic nucleoside derivatives using nucleoside drugs monocules as templates, and then tumor theranostic probe will be constructed through non-covalent modification of split aptamer with self-assemble nanoparticles by base interaction force; the cytotoxicity and biological effects of the probe will be explored, and the detection and therapeutic effects of self-assembly probe on tumor diseases will be discussed at the cellular and in vivo tissue level. This project will provide a new method and technology for developing simple and flexible aptamers probes for tumor diagnosis and treatment. It will be an innovative topic to promote tumor diagnosis and therapy in the cross field of nucleic acid chemistry and self-assembly technology.

设计并合成简单、灵活、高特异和高疗效的肿瘤诊疗探针在肿瘤疾病的检测与治疗领域具有重要的意义。本项目利用肿瘤激活式裂开型核酸适配体结合核苷衍生物自组装纳米颗粒，构建一种新型的核酸适配体功能化自组装体肿瘤诊疗探针。拟设计特异性靶向肝癌的裂开型核酸适配体探针，结合荧光淬灭、荧光能量共振转移等信号模式，构建具备多种信号模式的肿瘤激活式分子探针；拟选用核苷类药物小分子为模板，合成两亲性核苷衍生物，构建具备肿瘤治疗、碱基识别等多功能的自组装纳米颗粒，通过碱基相互作用力非共价修饰裂开型核酸适配体，实现肿瘤诊疗探针的构建；进一步探讨该探针的细胞毒性与生物效应，在细胞水平及活体组织水平探讨自组装体探针在肿瘤疾病方面的检测与治疗作用。本项目为发展简单、灵活的核酸适配体功能化的肿瘤诊疗探针提供了新方法和新技术，将是一项在核酸化学和自组装技术等交叉领域推动肿瘤诊疗学的创新性课题。

设计简单而特异的分子靶向探针和药物载体在肿瘤检测和治疗领域具有重要意义。本项目围绕裂开型核酸适配体肿瘤诊断与治疗探针设计、核苷衍生物自组装纳米颗粒的合成以及裂开型核酸适配体功能化纳米组装体的构建与应用等问题，利用裂开型核酸适配体作为识别分子，利用其设计灵活、靶诱导聚集等特性，构建了一系列用于肿瘤特异性靶向检测的激活式裂开型核酸适配体探针，采用核苷类药物制备两亲性核苷衍生物组装单元，构建了两种具备肿瘤治疗、药物装载等功能的纳米组装体，并进一步结合裂开型核酸适配体探针及自组装技术，发展了一种简单、灵活的裂开型核酸适配体功能化的自组装型肿瘤诊疗探针，在细胞水平层面上实现肿瘤的高特异、高灵敏、低毒副作用、高疗效诊断与治疗。该裂开核酸适配体探针体系构建简单、设计灵活，在临床肿瘤快速检测和精准治疗领域有一定的应用潜力。