侧链含寡肽温度和pH双重敏感聚合物的研究

Dual pH- and thermo-responsive polymers have found extensive applications in tissue engineering, drug delivery, and biosensors. Recently, much attention has been devoted to preparing poly(meth)acryl derivatives containing amino acids or oligopeptides in their side chains. The primary reason is for the advantage of amino acids including biocompatibilities, high-ordered structures, optical activity, and the precise controll over polymer composition and architecture via controlled radical polymerization(CRP). However, only two types of amino acid side-chain polymers exhibit dual pH- and thermo-sensitivities, one is aspartic acid,the other is five peptide sequence (VPGVG)in elastin. Moreover,these polymers only display thermo-sensitivities in acidic water due to the nature of carboxyl group, and are usually prepared in organic solvent. In this project, we will attempt to expand the type of amino acid as well as the pH range for thermo-sensitivity.We will utilize CRP in water to prepare dual stimuli-responsive homopolymers from a single molecule. This project will carry out the following work: (1) We will design and synthesize novel monomers based on oligopeptides, especially monomers bearing amine group. (2) We will employ CRP in water to obtain well-defined polymers. Then the effects of amino acid structures, length of oligopeptide, structures of substitutes and solution pH on dual stimuli-responsive properties will be investigated. Furthermore, the relationship between the variation of structures and dual-responsive properties of polymers will be revealed. (3) We will synthesize block copolymers from the novel monomers and investigate their micellization behaviors upon external stimuli. The present project will propose a new idea and method for the stimuli-responsive polymers to achieve high-performance.

温度和pH双重敏感聚合物已广泛应用于基因工程及药物释放等领域，在这类聚合物侧链引入寡肽或氨基酸是研究热点之一。因为氨基酸具有手性、生物相容性以及二级结构丰富等优点,而可控自由基聚合（CRP）在材料合成方面优势明显。已报道的温度和pH双重敏感氨基酸单体只有天冬氨酸和弹力蛋白五肽，且材料仅在pH<4的酸性水溶液中具有温敏性；此外，单体多在有机溶剂中聚合，以水为溶剂的研究才刚起步。因此，拓宽响应性氨基酸种类并采用新方法合成材料意义重大。基于此,本项目拟开展如下研究：1）设计并合成含寡肽的温敏性单体，拓宽材料pH响应范围；2）利用水相CRP技术制组成及结构精确的聚合物。系统研究寡肽氨基酸种类、聚合度以及构型对材料双重敏感特性的影响，阐明材料结构与性能的关系；3）合成基于寡肽单体的嵌段聚合物并研究其胶束化行为。该项目的实施，能够为刺激响应聚合物的高性能化提供新方法和思路。

以氨基酸或多肽构筑温度和pH双重敏感聚合物可以将聚合物的多样性与氨基酸的优点结合起来。然而已报道的温度和pH双重敏感氨基酸单体只有天冬氨酸和弹力蛋白五肽，且材料仅在pH<4的酸性水溶液中具有温敏性。基于此，本项目开展了以下工作：1）基于分子设计理念，合成了多种含氨基酸及寡肽的阳离子单体，采用NMR、HRMS以及FTIR表征了单体结构,得到了碱性环境里具有温敏性的寡肽及氨基酸衍生物，拓宽了温敏性聚氨基酸pH响应范围；2）采用水相可控自由基聚合技术得到结构和组成精确的聚合物，优化了聚合参数和条件；3）系统研究了氨基酸、寡肽以及取代基对聚合物刺激响应性的影响规律, 在此基础上总结了材料结构与性能的关系，为多重响应性材料合成提供了新思路；4)表征了聚合物疏水相互作用、聚合物与水分子之间氢键、侧链寡肽二级结构以及聚合物所有质子化学环境随温度的变化规律，揭示聚合物温度敏感源于疏水相互作用驱动并伴随着去水合化过程与相分离过程；5）以聚乙二醇为亲水链段构筑了刺激响应性AB两嵌段以及ABC三嵌段聚合物，研究了嵌段聚合物水溶液在刺激诱导下的胶束化行为及再组装机理；6）设计并合成了基于氨基酸的多重刺激响应性水凝胶，并利用合成的氨基酸单体采用水相RAFT聚合诱导自组装的方法合成了纳米凝胶。系统研究了其在溶液温度、pH值、离子强度等刺激诱导下的可逆溶胀与收缩，并探讨了这种变化对药物分子的可控装载与释放行为。本项目的实施为刺激响应聚合物的高性能化提供了新方法和思路。