多功能核酸适体探针的构建及其在肿瘤细胞靶向治疗中的研究

Cancer is a major disease that is harmful to human health. At present, the treatment of cancer confronts with two prominent problems. One is the resistance to chemotherapeutic agents. The other one is the low efficiency of delivery. This project intends to develop a multifunctional aptamer platform to realize the combined therapy, providing a new protocol to solve the above problems. This project takes advantage of the specific recognition ability of aptamer, the prolonged DNA obtained through the template-independent polymerization of terminal deoxynucleotidyl transferase as the loading unit and leading unit, the high loading capability and biocompatibility of nanoscale metal organic frameworks, constructing a target guided, high loading drug delivery system. The precise release is granted by the specific recognition ability of aptamer, and the multiple kinds and high loading of drug grant a successful combined therapy. All the efforts contribute to overcome the resistance problem. The synthetic procedure is quite simple, the biocompatibility of nucleic acid and nanoscale metal organic frameworks is reasonable, and this treatment platform is low toxic and highly efficient, providing a new method for the efficient treatment of cancer.

癌症是危害人类健康的重大疾病, 目前癌症治疗面对两个突出难题，一是细胞的抗药性，二是药物不能高效输送至病灶区域进行释放。本项目拟开发多功能核酸适体治疗平台，实现肿瘤细胞的联合治疗，为解决上述难题提供新方法。本项目拟选择核酸适体作为识别单元，通过末端脱氧核苷酸转移酶无模板扩增出的长链DNA作为载药单元和牵引单元，具有高效负载能力和强穿膜能力的纳米金属有机框架化合物作为药物载体单元，构建目标靶向、高通量输送药物的多功能核酸适体治疗系统。核酸适体的识别能力可保证药物精准输送，多种类高通量的药物可以实现化疗-光动力治疗的联合治疗，有力解决细胞抗药性问题。多功能核酸适体合成步骤简单，核酸和单元纳米金属有机框架化合物生物相容性好，由此构建的肿瘤治疗平台毒性低效率高，为癌症的高效治疗提供了新方法。

本项目基于功能核酸和纳米金属有机框架，通过设计和合成不同结构特性的纳米金属有机框架，优化其与核酸的连接方法，成功构建了新型多功能探针。基于核酸适体及末端脱氧核苷酸转移酶无模板扩增方法，实现了生命活动中重要生物大分子的高灵敏与特异性检测。主要成果包括：（1）基于新型鸟嘌呤四链体与切刻酶引导的核酸扩增技术，实现了对目标核酸和蛋白的高灵敏、高特异检测；（2）基于核壳结构构建的层状MOF的合成方法，合成薄层UiO-66-NH2具有高效催化活性和分离属性；（3）构建了核酸-金属纳米有机框架复合物，获得了稳定、高效的连接方法，该纳米复合物在检测、肿瘤靶向治疗的研究。通过该项目，发表SCI学术论文5篇，授权发明专利1项，申请发明专利3项，培养2名研究生。该工作发展了核酸、蛋白检测的新方法，层状金属有机框架合成的新方法，同时也为金属有机框架的功能纳米复合物在化学生物传感领域的研究提供了重要的参考价值。