基于响应性聚合物组装体构建可调控人工酶纳米反应器

According to the requirements and principles of "green chemistry", in view of the drawbacks of the amphiphilic supramolecular assemblies when acting as nanoreactors for organic catalytic reactions, such as the lack of structural stability, the incapability of stimuli-responsive adjustment and fulfilling multi-step tandem reactions in different solvents, we attempt to synthesize a series of amphiphilic stimuli-responsive block copolymers, in which the catalytic groups or “tracelessly” crosslinkable groups are caged by stimuli-responsive functional groups and integrated into the side chains of the hydrophobic blocks. After self-assembling into micellar or vesicular nano-assemblies, the catalytic groups or crosslinkable groups can be decaged via the removal of the stimuli-responsive functional groups triggered by external stimuli. The concentration of the catalyst groups, as well as the crosslinking degress, permeability and hydrophobicity/hydrophilicity of the reaction domains in the assemblies can be modulated by means of changing the triggering factors. Taking aldol condensation, Diels-Alder cycloaddition, etc. as model reactions, the reaction kinetics and mechanism of the one-step and two-step reactions occurring in the nanoreactors can be researched thoroughly. Besides, the artificial metalloenzyme nanoreactors will be constructed from the stimuli-responsive polymers for intracellular biorthogonal reactions triggered by the intracellular microenvironment with high-efficiency. Thus, the in-situ synthesis of fluorescent dye or chemotherapy drug molecules in the cells can be fulfilled, and the potential in vivo application of the metalloenzyme nanoreactors will be further explored.

本着“绿色化学”的原则和要求，针对目前应用于有机催化反应的两亲性超分子组装体纳米反应器结构稳定性不足且不可响应性调控、不能完成不同溶剂体系中的多步串联反应等问题，拟合成系列具有刺激响应性的两亲性嵌段共聚物，通过共聚功能化单体在疏水嵌段中引入被响应性基元保护的催化剂基元或可“无痕交联”基元，在组装形成胶束或囊泡结构组装体后，通过外界条件刺激触发响应性保护基元的脱除，释放出具有催化活性或交联反应活性的功能基元，通过改变触发条件调控反应微区内的催化剂基元含量、交联程度、渗透性、亲疏水性等，以羟醛缩合、Diels-Alder加成等为模型反应，探索研究一步反应、两步串联反应等的反应动力学和反应机制。此外，将基于响应性嵌段共聚物构建能够被细胞内微环境触发的人工金属酶纳米反应器，在其中进行高效生物正交反应，在细胞内原位合成荧光染料分子或化疗药物分子，并进一步探索其在生物活体内应用的可能性。

本项目针对目前的两亲性嵌段共聚物纳米组装体在用作有机化学纳米反应器时存在的结构稳定性和可调控性不足、不能实现不同溶剂体系下的多步串联反应等缺陷开展研究工作，结合紫外光和近红外光辐照、氧化性和还原性条件变化等多种响应机制，合成了系列结构明确、具有环境刺激响应性的两亲性嵌段共聚物，经自组装得到胶束、囊泡等不同形貌的超分子组装体，以这些超分子纳米组装体作为阿霉素(DOX)、喜树碱(CPT)等化疗药物和一氧化碳(CO)、一氧化氮(NO)等气体信号分子的载体及反应器，在多种(光照、氧化还原、pH等)不同刺激条件下触发共聚物的侧基或主链发生化学结构的变化，从而对组装体的形貌及其结构稳定性和渗透性进行调控，实现了负载于其中的化疗药物分子和CO、NO等的可控释放、协同治疗及成像试剂的响应性成像增强；进一步可在其中完成一步或多步有机、正交化学反应，在细胞内原位生成荧光成像试剂或化疗药物分子，实现对病变组织或肿瘤组织的原位诊断或治疗，体现真正的“绿色化学”理念和思想。