响应性聚合物纳米载体稳定性和药物控释/成像性能的同步调控

The ideal diagnostic & therapeutic systems based on nano-assemblies of block copolymers should satisfy the requirements of high structural stability, stimuli-responsive drug release and enhanced imaging properties. However generally, there are dilemmas between the structural stability and the drug release rate, as well as the enhancement in imaging properties. With the aim of solving these problems, we attempt to synthesize a serious of stimuli-responsive amphiphilic block copolymers, in which the oxidation-reduction or light-sensitive trigger moieties are designed to cage the primary amino groups in the side chains of the hydrophobic blocks. Fluorescence or magnetic resonance imaging moieties that can respond to the change in the surrounding microenvironment are also introduced into the hydrophobic blocks of the copolymers. Based on these amphiphilic block copolymers, nano-assemblies integrated with fluorescence or magnetic resonance imaging property and controlled drug release can be obtained. After being internalized into the tumor cells, the trigger groups can undergo stimuli-responsive dissociation and structural arrangement to decage the primary amino groups, which can induce the subsequent crosslinking between the copolymer chains to stabilize the nano-assemblies. At the same time, due to the protonation of the unreactive primary amino groups, the hydrophobic-hydrophilic transition can occur within the hydrophobic region of these nano-assemblies resulting in effective drug release; and the release process can be tracked in real-time via the change in the fluorescence emission or the MRI contrast. Therefore, multiple functions of biological stimuli-responsive therapy and diagnostic imaging can be fulfilled.

理想的基于嵌段聚合物组装体的纳米诊疗体系需同时满足结构稳定以及响应性触发释放药物和成像增强等条件，但稳定性提高与药物触发释放、成像增强等在设计上存在矛盾。针对这一局限性，本项目拟设计合成多种刺激响应性两亲性嵌段共聚物，在疏水嵌段引入可在氧化-还原性环境或光照条件下发生响应性解离的触发基元以保护侧链上的伯氨基团，同时引入可以对微环境变化产生高灵敏度响应的荧光成像基元和磁共振造影剂基元等；基于这类嵌段共聚物构筑兼具药物控释和成像功能的多功能纳米组装体，它们被肿瘤细胞摄入后，发生触发基元的生物环境响应性解离和结构重排并释放出伯氨基团，进而发生分子链间交联反应使组装体的结构稳定性提高，同时组装体疏水微区发生疏水-亲水转变，从而有效调控负载药物的释放并通过荧光和磁共振信号的变化进行实时跟踪，实现生物环境响应性治疗/成像复合功能。

针对由常规两亲性嵌段共聚物自组装得到的纳米医药载体在结构稳定性和渗透性之间的矛盾，为了实现组装体内负载的抗肿瘤药物的可控释放及协同成像增强，设计合成了一系列可对肿瘤组织/细胞内的特殊微环境，如弱酸性pH值、高巯基化合物浓度、高过氧化氢浓度等，具有刺激响应性的两亲性嵌段共聚物，并由其自组装得到胶束或囊泡结构的刺激响应性纳米载体。利用组装体疏水微区内的刺激响应性基元在肿瘤组织/细胞内特殊微环境作用下的解离、重排等反应，释放出伯氨等可交联官能团，进而通过与邻近链段侧基中酯键之间的酰胺化反应实现胶束内核或囊泡双层膜的交联，以提高组装体的结构稳定性。同时，利用未发生反应的部分伯氨基团的质子化过程，使组装体疏水微区发生疏水-亲水转变，增强其渗透性，实现组装体内所负载的抗肿瘤药物的控制释放。而在另一方面，组装体内荧光或核磁共振成像基元的响应性信号增强则可用以监控药物的输运及释放过程。此外，还设计合成了系列刺激响应性核交联胶束和聚离子复合物胶束，利用其对肿瘤组织/细胞中特定刺激信号的响应性，实现抗肿瘤药物或基因药物的有效输运/转染及控制释放。