生物相容改性葡聚糖大分子-氨基酸型二聚体表面活性剂聚集体结构的调控机理

The construction and microstructural control of biocompatible aggregates are very hot topics in multi-disciplinary areas, for example,solution and colloid, biological chemistry, and medicine.They provide a key route in developing novel types of aggregates as drug delivery vectors.This project will address initially to design and synthesize amphiphilic macromolecules with very good biocompatibility, i.e. the water-soluble dextran modified with bile acid and geminis including amino acids. We will characterize their physical-chemical properties and the possibility of aggregation in aqueous solution. For the mixed complex systems consisted of the modified dextran/amino-gemini,we will study their thermodynamic characterization of molecular self-assembly and phase behavior by high-sensitivity microcalorimetry, a variety of spectroscopic techniques, along with various microscopic techniques. We will discuss and evaluate comprehensively the effects of molecular structure on the molecular self-assembly process, including the hydrophobic side chains and the degree of substitution of modified dextran, and the spacer and hydrophobic chains of gemini. Also the effects of the composition,concentration and pH of the solution and temperature will be considered. Further the synergy of various couples with oppositely charged amphiphilic molecules will be compared in detail and generalized, and thus the thermodynamic model of the interaction will be proposed. As a result we can make use of these aggregates to carry out the attempt on model drugs. We will address the encapsulation of different polyphenolic drugs, characterize their properties, and propose in addition the mechanism of interaction between drugs and aggregates. All the results obtained from the studies on thermodynamics and microstructure will provide a new insight on theoretical and practical aspects for the control on formation of aggregates, which is very important to develope novel types of aggregates with potential application.

生物相容聚集体的构建及结构调控是溶液、胶体、生物、医药等相关学科的热点课题， 是发展聚集体药物载体的关键所在。本项目拟设计、合成有良好生物相容性的双亲分子- - 水溶性的胆汁酸疏水改性葡聚糖和氨基酸型二聚体表面活性剂，表征它们在水溶液中的物理化学性质和聚集能力；建立由不同的生物双亲分子构成的复杂体系，通过现代高灵敏的量热方法与光谱法及各种显微技术相结合，研究其分子聚集的热力学特性和相行为。深入了解双亲分子疏水侧链性质、间隔基团、替代度、电荷、溶液的组成、浓度、pH、温度等因素对复杂体系中分子聚集过程的影响；比较不同聚集体体系中各种双亲分子间的协同效应，建立相互作用的物理和热力学模型。将对构建的聚集体体系进行模型药物（类黄酮类）尝试，了解药物和聚集体的相互作用机理。这些结合宏观热力学和微观结构研究得到的结果，对聚集体的形成、功能化调控、开发和利用，具有重要的理论和实际意义。

合成了系列生物相容双亲分子胆汁酸改性葡聚糖和表面活性剂。建立了由单一、两种甚至三种双亲分子构成的仿生功能聚集体。以量热法为关键技术，与光谱法及显微技术相结合，通过宏观热力学和微观结构研究，揭示了这些双亲分子之间、聚集体与大分子或药物之间的相互作用热力学机理及聚集特性。(1)从量热方法直接获得了胆汁酸盐 (NaC，NaDC)两种聚集形态形成的重要热力学参数，揭示了熵驱动的预胶束和熵焓共同驱动的胶束形成机理，首次从热力学角度证实了胆汁酸盐的分步聚集模型。(2)系统地研究了胆汁酸盐与SDS的面-链疏水作用、与gemini表面活性剂的面-链疏水/静电协同作用以及 SDS/gemini静电作用。(3)用胆汁酸改性葡聚糖对表面活性剂聚集体进行表面修饰，将聚合物骨架的定域性能和表面活性剂的自组装性能结合构建了新的聚集体系。同时利用Gemini双极性头双疏水尾的双作用位点的交联作用，调控双亲聚合物的微结构。由此得到了各种聚集形态、临界浓度和聚集焓变。与胆酸盐/gemini体系比较，深层次地认识了聚合物分子骨架对分子间相互作用热力学机理的影响，揭示了Gemini的间隔基团、电荷密度、聚合物改性基团性质及替代度等对聚集体微结构调控的影响。(4)将量热技术应用于三组分双亲分子体系(polymer/gemini/SDS)，研究了更复杂的聚集体系(如混合囊泡)的相互作用热力学，这是在量热方法学上新的扩展。(5)基于双亲聚集体的增溶性和溶解平衡，对水难溶性药物(Rutin)的包埋和缓释及水溶性蛋白质药物的加载进行了尝试研究。结果表明Rutin在被研究的双亲聚集体中增溶量高达十多倍。首次通过溶解量热法获得了Rutin在这些聚集体系中的溶解焓。研究了双亲分子聚集体对于模型药物α-糜蛋白酶和过氧化氢酶的活性、稳定性及构象的影响。项目获得的研究结果为新型双亲分子仿生聚集体的研发提供了参考依据，为深层次的药物加载和输送研究奠定了基础。我们按计划完成了拟定的研究目标，也为开发双亲分子/药物体系新的研究课题提供了可行性，一些关键问题正在进行理论和实验的探索工作。