核酸适配体修饰的磁性介孔氧化硅复合纳米材料的制备及在非水溶性抗癌药物靶向输运中的应用

Low solubility in water is an intrinsic property of many anticancer drugs, which hinders the clinical use of those active ingredients. In addition, due to the nonspecific biodistribution of the drug in both cancer cells and normal tissues, anticancer drugs have been associated with significant toxicities to rapidly proliferating cells, such as nephrotoxicity and neurotoxicity. Targeted drug delivery is a method of delivering drug in a manner that increases the concentration of the medication in some parts of the body relative to others. For an effective drug delivery device, it is important to release the medication only under defined conditions, e.g. upon entrance into a cancer cell. The synthesis of such valves has become an interesting and widely investigated field of research. The features of mesoporous silica such as stable mesostructures, lack of cytotoxicity, large surface areas and tailorable pore sizes, make them excellent candidates for drug delivery and especially for delivery of hydrophobic agents. Aptamers are the synthetic DNA-based equivalent of antibodies and have unique molecular recognition properties, and improved stability. The construction of a drug carrier based on aptamer-modified mesoporous nanoparticles will provide a new opportunity to achieve targeted delivery and release of hydrophobic anticancer drugs. We seek support of this project for our exploration on synthesis of aptamer-conjugated mesoporous nanocarriers for drug delivery application. This research proposal puts forward a strategy to explore the preparation of magnetic core/mesoporous silica shell nanomaterials functionalized with aptamer, which is directly used for generating nanovalves that control the release of drugs in mesoporous nanoparticles. The overall purpose is to take an interdisciplinary approach, from materials synthesis to bio-evaluations, for the further development of nanocargos for targeted delivery and controlled release of insoluable anticancer drugs.

低水溶性是很多抗癌药物的本征性质，这一缺点阻碍了其活性成分临床应用的效果。此外，由于抗癌药物在癌症细胞和正常组织中存在非特异性生物分布，对易于迅速增殖的细胞容易引起毒性。介孔氧化硅稳定的多孔结构、无生物毒性、大的表面积和可调的孔径，使得这类材料成为药物输运，特别是非水溶性药物输运载体的最佳选择。核酸适配体是近年发展起来的新型识别分子，折叠形成特定三维结构与生物靶标高亲和力和高特异性结合，与抗体相比有自身的很多优势。本项目提出了一种核酸适配体功能化的磁性介孔氧化硅纳米粒子构建的药物载体的设计和制备，通过结合核酸适配体对癌细胞的靶向功能和介孔氧化硅对疏水性抗癌药物的载带功能，获得用于非水溶性抗癌药物靶向输运和可控释放的纳米器件。项目将对这种非水溶性抗癌药物靶向输运器件的制备技术、靶向输运药物、药物控制释放动力学等开展深入系统的研究，为基于介孔氧化硅的纳米生物医学功能器件的开发打下基础。

医学诊疗技术的进步是人类生命健康的重要保障，因此疾病诊疗相关基础研究工作一直备受关注。蛋白质是生命活动的主要承担者，疾病的发生发展与蛋白密切相关，申请人以疾病相关蛋白为研究对象，结合自己在核酸化学和无机功能材料设计和制备方面的优势，系统开展了疾病分子机制研究、疾病诊断和治疗这三方面的研究工作。具体来说，申请人通过结合核酸适配体对癌细胞的靶向功能和介孔氧化硅对疏水性抗癌药物的载带功能，获得用于非水溶性抗癌药物靶向输运和可控释放的纳米器件（Yuan Quan* et al. Chem. Commun., 2013, 49, 5823-5825）。除传统的化疗外，申请人以上转换纳米材料作为光动力学治疗中光敏剂的激发光源，以核酸适配体作为引导光敏剂的靶向试剂，构建了一种近红外光控制的靶向光动力学治疗系统（Yuan Quan* et al. Angew. Chem. Int. Ed., 2013, 52, 13965-13969）。该系统能特异性识别白血病细胞并在近红外光激发下产生单线态氧杀死癌细胞，对深层肿瘤的靶向治疗具有潜在价值。疾病分子机制研究是开发有效的疾病诊断和治疗方法的重要保障，而疾病的发生往往与蛋白质表达和活性异常密切相关。申请人完成了核酸适配体功能化金纳米棒在蛋白质活性可逆调控和针对靶向蛋白质体外成像方面的研究工作（Yuan Quan* et al. J. Am. Chem. Soc., 2015, 137, 10576-10584；Yuan Quan* et al. Angew. Chem. Int. Ed., 2014, 53, 1616-1620）。这方面的研究不仅可以辅助阐明疾病发生分子机制，进行疾病体外诊断，还对生命活动分子机理研究、代谢调节等基础研究有重要意义。申请人以第一/通讯作者在J. Am.Chem. Soc. (1篇)，Angew. Chem. Int. Ed. (2篇)，ACS Nano(1篇)，Anal. Chem. (1篇)，Chem. Commun. (1篇)等杂志发表论文14篇，做邀请报告8次，获得4项国家级人才计划资助（教育部新世纪优秀人才支持计划、国家优秀青年科学基金、第二批中组部万人计划青年拔尖人才支持计划、中国化学会青年化学奖），培养已毕业硕士研究生2名。