刺激响应性聚合物材料及其应用的研究

Stimuli-responsive polymer materials are playing an increasingly important part in the field of biotechnology and nanotechnology, such as drug delivery, diagnostics, gene engineering and smart optical systems, as well as biosensors, coatings and textiles. Of all these polymer materials, hybrid materials based on poly(N-isopropylacrylamide)(PNIPAm) probably belong to one of the most largest classes due to the sharp phase transition of PNIPAm at lower critical solution temperature (LCST). However, it is not easy to study these materials, because of the complexity originated from multi components, multi length scales and time scales of these systems. As experimental methods for studying dynamics and structure of these materials remain not complete, it is useful to adopt theoretical and computational approaches with all the interactions involved to visually predict and explain the physical processes. Although various of theoretical and computational techniques such as analytical theories, atomistic simulations and coarse-grained molecular simulations have been developed, there still exist limitations for each method. We aim to develop a molecular theory, including as many molecular details as possible, to systematically study:(i) The temperature-controlled ligand-receptor binding of streptavidin to biotinylated PNIPAm, which is often disregarded when explored in biosensor designs, but may directly determine the sensitivity of sensors.(ii) Dual temperature/pH-sensitive behaviors of DNA loading on a nanoparticle regulated by a grafted PNIPAm-b-PEI (polyethylenimine) layer, which may assist with the design of a new and optimal drug delivery system. The advantage of the molecular theory is the consideration of the conformation, size, and shape of each molecule and the combination of electrostatic interactions and steric repulsions in the system. The molecular theory should realize a molecular level description of these complexes and give a series of general guidelines for experiments.

基于聚(N-异丙基丙烯酰胺)(PNIPAm)的刺激响应性聚合物材料在药物运输、基因工程、智能光学系统、生物传感器等方面应用广泛。然而此类材料体系一般都具有组分多、协同相互作用复杂、时间尺度和空间尺度跨度大等特点，这给实验和理论的研究带来了很大难度。我们的目标是发展一套分子水平的理论来系统地研究：(i)链霉亲和素与绑定在PNIPAm聚合物刷自由端的生物素之间的特异性吸附(广泛应用于传感器设计)的温度响应性(直接影响传感器的灵敏度，由本项目首次提出)；(ii)表面嫁接PNIPAm-b-PEI的纳米颗粒运载DNA的温度/pH双响应行为(为新的多响应载药体系设计提供理论依据)。与一般的唯象理论不同：我们的分子场理论考虑了体系中每个分子的构象、大小和形状以及体系中的静电相互作用和排斥体积作用，能够从微观上揭示宏观实验观测量的物理本质，为实验和应用提供重要的理论依据。

刺激响应性聚合物材料在药物运输上应用广泛。其中，pH和温度刺激响应性的聚合物材料易于在活体环境中应用，提升药物运输效率，因此这些材料更具吸引力。然而此类材料体系一般都具有组分多、协同相互作用复杂、时间尺度和空间尺度跨度大等特点，这给实验和理论的研究带来了很大难度。本项目中，我们采用分子场理论研究了自由端修饰了蛋白质配体的PNIPAm聚合物刷温控溶液中的受体蛋白质的吸附量和吸附取向、PNIPAm端嫁接于电中性底板上的PNIPAm-b-PEI双嵌段共聚物刷温度/pH控制ssDNA的吸附量、PEI的吸附对带负电的纳米粒子电性、DNA压缩的控制。围绕本项目研究内容取得以下研究成果：（1）吸附于PNIPAm上配体的蛋白质的方向呈现三阶段的温度响应性；蛋白质吸附量取决于聚合物的面密度和蛋白质自身的大小和电性。这些结果的发现丰富了控制免疫蛋白质方向的方法，提升免疫传感的灵敏度。（2）吸附于PNIPAm-b-PEI双嵌段共聚物上的ssDNA呈现温度/pH双响应性；尤其当pH处于6.5-6.8（肿瘤细胞pH范围）之间，温度和pH对ssDNA的吸附量的调节能力相似，这对多响应性药物载体的设计具有重要意义。（3）吸附于纳米粒子表面的PEI改变了纳米粒子的有效半径和电性；当pH提高到一定程度，纳米粒子表面电性反转，由负电属性转变为正电属性，这有助于纳米粒子吸附到带负电的细胞膜上，提升运输效率；等电位点与纳米粒子本身电性以及PEI与纳米粒子表面相互作用有关；（4）吸附于ssDNA刷的PEI可实现DNA刷的压缩；压缩程度取决于pH、DNA面密度和长度以及PEI的长度；存在特定的pH使DNA压缩程度最大，这有助于保护DNA在运输中不被血清蛋白分解。上述研究成果为刺激响应性聚合物材料在药物运输方面的发展提供了重要理论依据。