可生物响应性调控的磁共振成像/药物输运复合功能核交联胶束纳米载体研究

In order to overcome major limitations of polymeric assemblies- based T1-type magnetic resonance imaging (MRI) contrast agents, such as weak structural stability, inefficiency in bioreponsive enhancement of MR imaging contrast, and low drug loading efficiency and uncontrollable drug realease when acting as drug delivery nanocarriers, in this application, we attempt to synthesize a series of bioresponsive macromolecular MRI contrast agents integreted with multiple functions of stimuli-tunable fluorescence emission and stimuli-triggered release of covalently conjugated drugs based on structurally stable core- crosslinked (CCL) micelles of diblock copolymers. The bioresponsive enhancement of MR imaging contrast can be attained by tunable changes in the surrounding microenvironment of DOTA(Gd) moieties induced by hydrophobic-hydrophilic transition of the pH-sensitive crosslinked core under mildly acidic conditions. We will then covalently conjugate NBD fluorescent moieties into the crosslinked core aiming to achieve pH-enhanced magnetic resonance and fluorescence dual-modality imaging. Furthermore, by combining bioresponsive magnetic resonance imaging with drug delivery and regulated drug release, thiol-sensitive functional nanomedicine system based on CCL micelles with integreted functions of MR imaging and drug delivery will also be prepared,in which the micellar core is crosslinked by a disulfide-containing crosslinker and anticancer prodrug moieties are covalently conjugated into the core, thus thiol-triggered MRI contrast enhancement and drug release can be achieved. The above research contents are expected to provide important reference for further optimizing the design of new generation macromolecular MRI contrast agents and nanomedicine systems.

针对基于高分子胶束组装体的T1型磁共振成像(MRI)造影剂存在的结构稳定性差、不能有效实现MRI信号的响应性增强以及作为药物载体时负载效率低和不可控释放等局限性，本项目拟合成一系列以结构稳定的嵌段共聚物核交联胶束为载体的生物响应性磁共振造影剂，并兼具可调控荧光成像和响应性释放共价键合药物的复合功能。利用pH响应性交联内核在弱酸性环境下发生疏水-亲水转变调控钆络合物造影基元所处的微环境，实现MRI信号的响应性增强；进一步在交联内核中引入NBD荧光基元，力图实现MRI/荧光双模成像的pH值响应性调控；还将融合MRI信号的响应性调控与新型药物负载/控释策略，采用含二硫键的交联剂进行核交联并在核内共价键接具有巯基响应性触发释放特性的抗肿瘤前药基元，合成巯基敏感的具有MRI造影增强/药物输运复合功能的诊疗体系。该项目的实施预期将为新型大分子造影剂和诊疗体系的设计和优化提供重要依据。

为了克服基于嵌段共聚物组装体的高分子纳米医药体系的结构稳定性差、作为药物载体时药物负载效率低和药物释放不可控，以及基于纳米组装体的T1 型磁共振成像(MRI)造影剂存在的不能有效实现MRI信号的响应性增强等的局限性，在本项目实施过程中，针对肿瘤组织和肿瘤细胞的微酸性、氧化还原性等特征，基于具有光响应性、pH或氧化-还原环境响应性的两亲性嵌段共聚物，结合嵌段共聚物自组装，采用外加交联剂进行化学交联的方法制备了一系列核交联或壳交联胶束,采用无外加交联剂的环境响应性“无痕”交联策略制备了系列囊泡或复合囊泡结构纳米组装体，以这些具有稳定交联结构的纳米组装体为平台，结合荧光成像的高灵敏度、高分辨率和核磁共振成像的非侵入性和优越的组织穿透能力等特点，构筑了能够在保持组装体结构稳定性的同时提高组装体渗透性，实现荧光-核磁共振双模成像功能响应性增强的载体体系，以及能够借助于荧光或核磁共振成像监测药物输运和响应性释放过程的纳米诊疗体系。相关研究结果为基于响应性嵌段共聚物组装体的纳米医药体系的设计和优化提供了新的思路和重要依据。