多重响应性纳米水凝胶杂化网络结构的调控及其基因药物控释性能

Multi-responsive hybrid nanohydrogels (MRHNHs) composed of functional inorganic nanoparticles (NPs) and cationic responsive hydrophilic (co)polymers are regarded as very promising nano-carriers for gene delivery. However, the wide application of the most of MRHNHs is suppressed by their poor structure stability in aqueous systems and fair controlled release behavior of incorporated drugs. In this project, structurally stable, magnetically oriented MRHNHs will be prepared through inverse miniemulsion copolymerization of functional monomers in the presence of vinyl- and amine-functionalized Fe3O4 NPs. The Fe3O4 NPs are chemically attached to the copolymers through the grafting reaction of Fe3O4 NPs. The hybrid network of the MRHNHs is crosslinked with vinyl-functionalized Fe3O4 NPs and a disulfide-containing small crosslinker. The structural stability and drug controlled release behavior of the MRHNHs will be effectively improved through adjusting the structures of hybrid network (the density and distribution of the crosslinking point, the ratio of two different crosslinking points, the copolymer composition, and the grid size of the network). We will focus on the investigation of the grafting reaction mechanism of Fe3O4 in inverse miniemulsions, the relationship between the grafting state of Fe3O4 (the grafting density, the length and crosslinking degree of the grafting chains) and the hybrid network structure of MRHNHs. A strategy to regulate the hybrid network of MRHNHs will be proposed. In addition, the relationship of the hybrid network, responsiveness, and drug controlled release behavior of MRHNHs will be thoroughly investigated. The research of this project can provide strong supports to the design, regulation, and optimization of nano-carriers for gene delivery.

由功能性纳米粒子和响应性聚合物构成的多重响应性杂化纳米水凝胶（MRHNH）是一类极具开发前景的基因药物纳米载体，但其应用时还普遍存在结构稳定性差、药物控释性不强等问题。本项目拟通过活性Fe3O4纳米粒子存在下的反相细乳液共聚合，实现Fe3O4与响应性聚合物的化学键联结，同时构筑由Fe3O4颗粒接枝（交联）和共聚链化学交联协同组成的杂化网络结构，再通过调控杂化网络结构（交联点密度及分布、两种交联形式比例、共聚链结构、网格尺寸等），有效提升MRHNH的结构稳定性和药物控释性。研究中重点关注反相细乳液这一新兴非均相聚合体系下Fe3O4的接枝反应规律、Fe3O4表面接枝状态（接枝密度、接枝链长度、接枝链交联程度等）对MRHNH杂化网络结构的影响规律及其调控机制、杂化网络结构—响应性—药物控释性三者间的内在关联。研究工作及其成果可为基因药物纳米载体的结构设计、调控以及性能提升提供理论基础和策略支撑。

本项目针对多重响应性杂化纳米水凝胶（MRHNH）存在的无机功能组分与响应性聚合物的复合结构不稳定、药物控释性不足的问题，基于异氰酸酯与羟基的反应，建立了Fe3O4表面高效、可控修饰的方法，实现Fe3O4表面乙烯基修饰状态的精确调控。以乙烯基修饰的Fe3O4为磁功能组分，响应性单体为主单体，采用含可断裂化学键的交联剂，构建了反相细乳液反应体系，分别利用自由基聚合和ATRP反应，高效制备了由Fe3O4和响应性聚合物杂化网络构成的结构稳定性好、响应能力强的MRHNHs。乙烯基修饰的Fe3O4在聚合过程中通过表面接枝反应接入杂化网络。在系统表征MRHNHs的微结构、颗粒结构的基础上，结合MRHNHs在不同外源条件下的响应行为，建立了MRHNHs结构与响应行为的对应关系。进一步，以抗癌药物和生物大分子为模型药物，系统研究了不同外源条件下，MRHNHs装载和释放模型药物的行为，并结合MRHNHs和模型药物的作用方式的研究，揭示了MRHNHs装载和释放模型药物的机制。作为本项目的拓展，在以O-羧甲基壳聚糖（OCMC）稳定的Fe3O4 MNPs水分散液为分散相的反相细乳液中，通过Schiff碱缩合反应，制备了具有结构稳定性好、pH响应、超顺磁和强磁响应性的OCMC/Fe3O4 MRHNHs。本项目的研究工作对于面向纳米药物传输应用领域的新型MRHNHs的结构设计、可控合成以及控释行为调控等方面有很高的参考价值和指导意义。