基于多级孔结构SiO2构筑具有双重环境响应性药物控释智能材料的制备与表征

Since the discovery of M41S mesoporous silica in 1992, mesoporous silica nanoparticles (MSN) have attracted numerous studies. However, normal MSN are unintelligent materials for the controllable release. To overcome the shortcoming, this project focuses on the introduction of advanced fractal dimension of concept and fractal geometry theory into the environmental response drug controlled release system, combined with other various characterization methods. By using temperature and pH dual-stimuli-responsive polymer (SRP) as shell and multi-scale dimension and hierarchical MSN as core, novel intelligent drug controlled delivery nanomaterials with environmental dual-stimuli-responsive properties and core/shell structure characteristic are designed and then prepared via polymerization technology by using Doxorubicin, Mitoxantrone, Fuorourac, Cimetidine and Taxol as drug model respectively.In the carrier system, the organic-functionally modified MSN is used as drug containers and the SRP grafted on the outside surface of MSN is employed as stimuli responsive switchable gates..In view of the above key sciences and important technologies, the multi-scale dimension and hierarchical MSN and the SRP are systematically researched including their structure morphology, surface defects, mesopores features and cross-linking networks. Meanwhile, the structurally controlled strategies of the mentioned above MSN and the assemble preparation conditions of adjusting hydrophilic/hydrophobic compositions of SRP are demonstrated, in which, particularly, their influence of loaded drug amount and the dual-pH and temperature response behaviors are investigated in details. So that, the reasonable arrange of the pore structure and the diffusion mechanism of the targeted the release profiles in different medium are put forward, which is in favor of improving the drug loading amount and clarifying influences of the surface functional groups grafted on the inner mesoporous channels of MSN and the hydrophilic/hydrophobic clusters existed in the SRP structures. Moreover, not only the intelligent properties, but also the composition-structure-performances relationships could be accurately described, which is very useful to understand the essence mechanism of controlled drug delivery derived from microstructure levels..Thus, the new method based on the fractal technology and corresponding new theory about multi-scale dimension and hierarchical mesoporous structure can be further developed, new viewpoint about "intelligent" mechanism may be suggested. In summary, based on the above all experimental and research results, this project could solve key technologies to prepare the environmental response intelligent nanomaterials in controlled drug delivery fields, and provide sufficiently theoretical basis and strong technical parameters in the biological chemical and related applications such as petrochemical industry and fine chemicals.

介孔SiO2纳米颗粒（MSN）被认为是重要的药物缓释载体之一，但迫切需要解决其"惰性"。本项目从结构设计与表征出发，将分形维数概念和分形几何理论运用到药物控释研究中，结合其他分析方法，以多尺度多维化MSN为核，对pH和温度具有双重响应聚合物（SRP）为壳，通过聚合技术，以盐酸阿霉素，盐酸米托蒽醌，氟脲嘧啶，西咪替丁和紫杉醇为模型药物，设计和制备出具有包覆结构的环境响应性药物控释智能材料。系统研究多尺度多维化MSN和SRP结构信息，调控措施和组装条件对载药量以及智能释放的影响，旨在实现多级孔的合理搭配，从而提高药物的装载量，澄清MSN表面官能团和SRP中亲水/疏水链的影响规律；提出吸附与扩散机制，藉此能够准确了解其 "智能"行为；揭示构效关系和控释本质；发展分形技术，为研发新型智能材料提供新的视角和思路。最终为解决药物控释材料关键技术以及在相关领域中的应用提供重要的理论依据和实验指导。

本项目首先通过自由基聚合原理考察了具有pH敏感型共聚物（PAA和PMAA）和具有温敏性共聚物（PNIPAAm）以及具有温度/pH双重敏感性聚合物（P(NIPAAm-co-AA）的制备、表征及其在不同环境（不同pH值和不同温度）下的溶胀-退溶胀性能，深入研究了葡聚糖(Dex)和丙烯酸(AA)单体添加量及盐离子强度和浓度对聚合物结构和智能行为的影响机制。然后选择典型介孔材料（BMMs， MCM-41和SBA-15）为基体、上述聚合物为包覆材料，设计和制备出具有多尺度多维化结构的环境响应性有机-无机纳米杂化材料。同时采用Stöber合成路线， 探讨了聚苯类或酚醛树脂类乳胶粒子表面性能和粒度形貌对介孔SiO2（BMMs和SBA-15）空心球空腔“核”和介孔“壳”的影响规律，阐述了介孔壳结构的制备规律和径向分布以及空腔“核”的控制措施，并提出合理的形成机理。以盐酸阿霉素，盐酸米托蒽醌，氟脲嘧啶，西咪替丁，紫杉醇以及阿司匹林和布洛芬为模型药物，重点研究了他们对药物的组装和释放性能。应用XRD， SEM/TEM，FT-IR，TG-DTG，N2-sorption，NMR，粒度分析，Zeta电位和荧光光谱等多种表征手段对共聚物、杂化材料以及药物装载与释放后的结构与性能进行了详细表征。布洛芬装载量达22.4mg/g，且具有较好的环境响应控释行为，尤其是PMAA的包裹抑制了释放初级阶段的“突释”现象。载药和释放动力学过程均符合Korsmeyer-Peppas模型，在酸性环境中，药物释放遵循“扩散控制”机理，在碱性环境中，释放过程则受“扩散控制”机理和浓度差的共同影响，从而提出了吸附与扩散机制。另外采用不同金属离子（Zn2+, Cu2+, Ni2+, Fe3+）改性1,8-萘二酸酐，并通过后处理方法嫁接在介孔SiO2表面，探讨了制备规律及其荧光性能，有利于明晰构效关系和控释本质。 特别是采用SAXS方法探讨了上述聚合物及其杂化材料的多尺度多维化孔道结构信息，应用分形理论，论述了表面分形（2.50-2.87）和质量分形（2.56-2.89）在载药和释放过程中的结构演变规律，为研发新型智能材料提供新的视角和思路。最终为解决药物控释材料关键技术以及在相关领域中的应用提供重要的理论依据和实验指导。