肺癌特异性核酸适体药物复合物的构建及机理研究

The high cost of antibodies and the toxic side effects of drugs have greatly limited the extension and application of most antibody-drug conjugates (ADC), while the Aptamer as a chemical antibody, is inexpensive and easy to be synthesized and modified. Aptamer-drug conjugates (ApDC) have been improved to some extent in recent years, however, the study on the mechanism of drugs internalization and action is relatively few. Earlier studies in our group found that Aptamer Ap3 could specifically identify lung cancer cell lines and tissues, it could specifically enrich in tumor site for 4 hours in the nude mouse transplanted tumor model. BAY11-7082, an inhibitor of NF-κB signaling pathway, was proved to suppress the lung cancer cell line proliferation and promote cell apoptosis effectively. Herein, we plan to construct an aptamer-drug conjugate with Ap3 and the BAY11-7082 by the solid phase synthesis process, and explore the internalization and action mechanism as well as the target therapy effect of this ApDC on NF-κB signaling pathway.

抗体的高成本及药物的毒副作用极大地限制了多数抗体药物复合物（Antibody-Drug Conjugates, ADC）的推广使用，而核酸适体作为化学抗体，成本低廉且易于修饰。核酸适体药物复合物(Aptamer-Drug Conjugtes, ApDC)近年来得到了一定的发展，但药物的内化及作用机制研究相对较少。本课题组前期研究发现，核酸适体Ap3能特异性识别非小细胞肺癌细胞及组织，在裸鼠移植瘤模型中能特异性在肿瘤部位富集，并且在肿瘤部位停留4小时左右。研究表明NF-κB信号通路的抑制剂BAY11-7082能抑制肺癌细胞的增殖，促进其凋亡。因此本项目拟以核酸适体Ap3为靶向肺癌的工具，与在抑制剂BAY11-7082进行连接，通过固相合成法构建新的核酸适体药物复合物，实现肺癌的靶向治疗，并对药物的内化、释放及作用机制进行探索。

近年来多种抗体药物复合物(Antibody-Drug Conjugates, ADC)被用于肿瘤的靶向治疗，但抗体的高成本及药物的毒副作用极大地限制了多数ADC的推广使用。核酸适体作为“化学抗体”，成本低廉且易于修饰。核酸适体药物复合物(Aptamer-Drug Conjugtes, ApDC)目前得到了一定的发展，但药物的内化及作用机制研究相对较少。该项目基于期研究发现：核酸适体Ap3能特异性识别结肠癌、非小细胞肺癌细胞及组织，在裸鼠移植瘤模型中能特异性在肿瘤部位富集，首先通过末端连接、固相合成以及PCR的方式构建ApDC，并考察了ApDC细胞水平的靶向性、毒性和内化效果；接着考察了ApDC对微管聚集、细胞凋亡等的影响以及内化进胞的途径；最后考察了ApDC在皮下移植瘤模型中的靶向性和治疗效果。该项目对ApDC的构建、ApDC的内化机制、ApDC的作用机制、靶向效果等进行了系统研究.丰富了ApDC的机制研究，为ApDC的临床转化提供了依据。