具有细胞内选择性输运和同步荧光触发特性的反应性高分子组装体构筑

Polymeric nanocarriers sensitively responding to tumor microenvironments could achieve selective accumulation and drug release at the disease site. By taking advantage of the high content thiol-containing bioactive molecules (e.g., GSH) within tumor cells, disulfide-containing polymeric drug nanocarriers have been designed, aiming to achieve site-specific drug delivery triggered by intracellular reductive microenvironments. However, the current design of reduction-sensitive polymeric nanocarriers mainly relies on equilibrium exchange reactions between free thiols and disulfide linkages. In this proposal, we attempt to design polymersomes of amphiphilic polymers which could react with thiol-containing bioactive molecules via Michael addition or nucleophilic substitution mechanisms. These high-efficiency reactions will trigger transformation of the microstructure and hydrophobicity/hydrophilicity of polymersome bilayers, thus modulating the release profile and membrane transport of encapsulated bioactive agents; concurrently, thiol-involved reactions will trigger prominent changes of fluorescence signals, achieving image-guided in situ monitoring of changes in polymersome permeability and drug release process; we attempt to further integrate enzymatic reactions and the triggering capability of enzymatic products, and to construct biomimetic nanocarrier systems exhibiting positive feedback and circle amplification features in the context of polymersome permeability, drug release rate, and the extent of fluorescence signal enhancement. Research results of this proposal are expected to provide new insights and important guide for the design of next-generation smart drug nanocarriers.

对肿瘤微环境具有灵敏响应的高分子纳米载体能够实现在病变部位的选择性富集和药物释放。基于肿瘤细胞内含巯基生物活性分子(如谷胱甘肽等)浓度较高的特点，能够设计含二硫键的高分子纳米药物载体并实现胞内还原性微环境响应的特异性药物输运。针对目前还原性响应纳米载体的设计主要依赖于二硫键-自由巯基平衡交换反应的局限性，本申请项目拟设计能与含巯基生物分子发生迈克尔加成/亲核取代反应的两亲性聚合物囊泡载体，利用这些高效化学反应触发囊泡双层膜的微结构和亲疏水性发生转变，以调控所负载活性物质的释放和跨膜传输；同时，含巯基分子参与的反应将触发荧光信号显著变化，从而实现囊泡渗透性和药物释放过程的可视化；还拟进一步结合酶催化反应和酶促产物的连锁触发能力，构建囊泡双层膜的渗透性、药物释放速率和荧光信号增强程度都具有正反馈和循环放大特征的仿生纳米载体体系。相关研究结果预期将为新一代纳米药物载体的设计提供新思路和重要参考。

利用肿瘤微环境激活纳米诊疗体系有利于实现肿瘤局部给药和实时反馈治疗效果，从而提高肿瘤疗效并降低系统毒副作用。本项目通过发展肿瘤微环境响应性功能基元，融合荧光信号调制，触发式自分解基元，酶催化反应，循环放大等概念，通过单体化或聚合物后功能化修饰途径构建新型的肿瘤微环境响应性聚合物；利用嵌段聚合物可控自组装构筑超分子组装体并实现生物活性分子的高效负载；超分子组装体通过细胞内在化进入胞质后，利用肿瘤特定微环境实现诊疗功能的选择性激活，触发所负载生物活性分子的选择性释放和成像造影功能增强。在项目执行过程中，成功发展了精准聚乙二醇 (PEG) 及其衍生物高效制备方法，成功发展了具有双重笼闭效应的连接子基元制备策略；提出了利用聚合物囊泡到聚离子复合物囊泡的转变实现囊泡渗透性的可控调节；发展了一系列 (氧化还原、醌氧化还原酶、光) 响应性诊疗体系实现了肿瘤的有效治疗。其中精准PEG及其衍生物的制备技术在纳米医药、能源存储与转化、航空航天等领域具有重要的应用前景。过去四年共发表基金标注论文25篇，包括Angew. Chem. Int. Ed. 3篇，Nat. Commun. 1篇，Adv. Mater. 1篇等，获授权发明专利6项，培养研究生7人，在国内外学术会议上作邀请报告10余次（含2次高登研究会议特邀报告）。