环境响应型DNA微凝胶载体的构建及在抗肿瘤药物可控靶向递送中的应用

Constructing delivery systems is one of the effective means to solve the key problems of low bioavailability, poor targeting and high toxic side effects of antitumor drugs. The existing antitumor drug delivery systems still have shortcomings in security, controllability and efficiency. It is necessary to develop new effective delivery systems for antitumor drugs. Based on the specific tumor microenvironment, the project is planning to design and prepare a series of three-dimensional porous DNA microgels with active targeting capability, multiple environmental (pH, glutathione and temperature) responsiveness and biodegradability. Antitumor drugs will be loaded into microgels efficiently through continuous adsorption process. Through specific recognition of aptamers, the drug delivery systems will actively target the tumor sites, and then control drug release in temporal-spatial dimensions. Microgels degradation will promote deep diffusion of antitumor drugs. Tracking of drug delivery process will be realized by labeling the microgels with fluorescence dye. This project will systematically evaluate the influence of delivery and therapeutic effects of DNA microgels for Dox, a model antitumor drug. A kind of safe and efficient delivery materials for antitumor drugs will be obtained after performance optimization. The intelligent DNA microgels delivery systems constructed in this project will have great theoretical significance and application value for improving the delivery effect and promoting the targeted therapy of antitumor drugs.

构建纳米递送系统是当前解决抗肿瘤药物生物利用度低、靶向性差和毒副作用大等关键问题的有效手段之一。现有的抗肿瘤药物递送系统在安全性、可控性和递送效率上仍存在不足，迫切需要发展安全、高效的新型抗肿瘤药物递送系统。本项目基于肿瘤微环境的生物学特征，设计并构建系列集主动靶向性、多重环境（pH、谷胱甘肽和温度）响应性、可降解性于一体的三维多孔DNA微凝胶载体，高效装载抗肿瘤药物，利用核酸适配体的特异性识别作用主动靶向至肿瘤部位并实现时-空维度上的控制释放，载体降解促进药物深度扩散，经荧光标记实现载药系统输送过程的追踪。以盐酸阿霉素为模型药，从分子、细胞、组织和整体动物四个层次系统评价DNA微凝胶对抗肿瘤药物的可控靶向递送及治疗效果的影响，经性能优化获得一类安全、高效的抗肿瘤药物递送材料。本项目研究的智能微凝胶递送系统对改善抗肿瘤药物递送效果、推动抗肿瘤药物的靶向治疗具有重要的理论意义和应用价值。

构建纳米递送系统是当前解决抗肿瘤药物生物利用度低、靶向性差和毒副作用大等关键问题的有效手段之一。现有的抗肿瘤药物递释系统在安全性、可控性和递送效率上仍存在不足，迫切需要开发安全、高效的新型抗肿瘤药物递释系统。本项目基于肿瘤微环境的生物学特征，设计并构建了兼具主动靶向性、三重环境响应性和可降解性的多功能DNA微凝胶来递释临床常用抗肿瘤药阿霉素，并且设计并构建了兼具双重靶向性、三重环境响应性和荧光成像能力的多功能DNA微凝胶来递释多靶点抗肿瘤中药藤黄酸。从分子、细胞、组织和整体动物四个层次系统研究了多功能DNA微凝胶递释系统对抗肿瘤药物阿霉素和抗肿瘤中药藤黄酸的精准靶向递送和可控释放的效果。结果均表明DNA微凝胶递释系统能够显著增强递送药物的抗肿瘤能力，具有很好的体内生物安全性，并且能够减少药物脱靶引起的毒副作用，提高了其生物利用度，对抗肿瘤药物起到增效减毒的作用。这种可靠且直接的制备多功能纳米递释系统的方法为未来设计适合临床应用的新型抗肿瘤治疗递送系统奠定了基础。在递送抗肿瘤药物中展现出巨大的潜力和优势。为构筑安全、高效的纳米递释系统提供新思路和新策略。本项目的研究成果申请中国国家发明专利2项，发表学术论文9篇，其中SCI收录5篇，2篇为中科院大类一区top期刊。发表学术会议论文2篇。培养硕士研究生3名。获批天津市应用基础研究项目1项。本项目注重了学科交叉，完成了原定计划，研究结果对新型抗肿瘤药物递释系统的创制和促进抗肿瘤药物的临床应用具有重要意义。