基于核酸适配体识别的肿瘤靶向自组装DNA纳米笼载药系统的研究

As a specific, high affinity targeting molecule, aptamers are of potential applications in tumor-targeting drug delivery system. However, most aptamers inclined to degradation in vivo by nuclease, not directly penetration into cells and require complex chemical modification for connecting with other drugs or carriers. In this study, tetrahedral DNA cage were introduced as a drug carrier to connect with an aptamer to construct the aptamer-recognized aptamer-tetrahedral DNA cage drug carrier. The properties of tetrahedral DNA cage tend to protect nucleic acid molecule form degradation and easily uptake by cells were utilized to make up the shortcomings of aptamers as targeting molecules. Moreover, Doxorubicin, as a model drug, was linked to the aptamer-tetrahedral DNA cage by non-covalent or covalent ways to establish aptamers recognized tumor-targeting DNA cage drug delivery system. This system can be prepared by self-assemble of the nucleic acid backbone contain aptamers DNA fragment, without complicated steps of chemical modification. Due to the targeting effect of aptamers, this system can achieve targeted drug delivery to tumor cells, which provide a novel drug delivery system for chemotherapy drugs to realize tumor-targeting delivery.

核酸适配体作为一种特异性强、亲和力高的靶向分子，在肿瘤靶向药物传递系统中具有很好的应用前景。然而，多数核酸适配体存在易被体内核酸酶降解、不能直接进入胞内和与其他药物或载体连接时需要复杂的化学修饰的问题。本课题通过引入正四面体DNA纳米笼作为药物载体，将其与核酸适配体靶向分子结合，利用正四面体DNA纳米笼具有保护核酸分子不易被降解的特性以及易于被细胞摄取的能力，弥补核酸适配体作为靶向分子的缺点，从而构建一种基于核酸适配体靶向的适体-正四面体DNA纳米笼药物载体。以多柔比星为模型药物，通过非共价及共价两种方式与适体-正四面体DNA纳米笼结合实现载药，建立基于核酸适配体识别的肿瘤靶向DNA纳米笼递药系统。该系统可通过包含有核酸适配体的DNA纳米笼核酸骨架自组装形成，无需复杂的化学修饰制备步骤，并可通过核酸适配体的靶向作用实现对肿瘤细胞的靶向递药，为化疗药物的肿瘤靶向递送提供一种新的载药系统。

核酸适配体作为一种特异性强、亲和力高的靶向分子，在肿瘤靶向药物递送系统中具有很好的应用前景。然而，多数核酸适配体存在易被体内核酸酶降解、不能直接进入胞内和与其他药物或载体连接时需要复杂的化学修饰的问题。本项目通过引入正四面体DNA纳米笼作为药物载体，将其与核酸适配体靶向分子结合，利用正四面体DNA纳米笼具有保护核酸分子不易被降解的特性以及易于被细胞摄取的能力，弥补核酸适配体作为靶向分子的缺点，从而构建一种基于核酸适配体靶向的适体-正四面体DNA纳米笼药物载体。首先以正四面体DNA纳米笼核酸骨架为基础，选择MUC1适体作为靶向分子，同时考虑到适体引入可能对DNA纳米笼自组装造成影响，在MUC1适体与DNA纳米笼基本骨架序列之间添加linker序列，完成了自组装DNA纳米笼骨架序列的设计与筛选。其次以四条DNA单链为原料，利用PCR仪分别合成了顶端修饰有不同个数MUC1适体的正四面体DNA纳米笼，构建了正四面体DNA纳米笼肿瘤靶向载体系统，并对其形态、稳定性、细胞毒性、细胞摄取等性质进行了表征，结果表明适体修饰的DNA纳米笼生物相容性好，且对MCF-7细胞有较好的靶向性。最后以多柔比星为模型药物，通过非共价方式与适体-正四面体DNA纳米笼结合实现载药，建立了基于核酸适体识别的肿瘤靶向自组装DNA纳米笼递药系统，并对该载药系统的释药行为、体内外靶向性及抗肿瘤活性等进行了评价，结果表明载药DNA纳米笼在体内发挥良好的肿瘤治疗效果的同时，增加药物在肿瘤细胞内的累积，大大降低了对正常组织的毒副作用。我们建立的基于核酸适配体识别的肿瘤靶向自组装DNA纳米笼载药系统可通过包含有核酸适配体的DNA纳米笼核酸骨架自组装形成，无需复杂的化学修饰制备步骤，并可通过核酸适配体的靶向作用实现对肿瘤细胞的靶向递药，为化疗药物的肿瘤靶向递送提供一种新的载药系统。

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