基于单分散氧化石墨烯药物控释胶囊的构建与特性研究

Thin layer graphene oxide (GO) micro-/nano-sheets have planar structures with the thickness of a few carbon atoms, capable of loading hydrophobic drugs through interactions including π-π electrons stacking. The repulsion of surface charges on GO sheets separates them from each other, thereby increasing the solubility of hydrophobic drugs. However, compared to other micro-/nano-particles, a key scientific issue is whether GO sheets have distinguished characteristics for drug loading and controlled release. In this project, 3-6 kinds of monodisperse GO sheets in the range of 2 μm - 50 nm will be prepared for hydrophobic drugs loading, and used as cores to assemble different substituents of chitosan / sodium alginate biological macromolecules, as well as gold nanoparticles in shells, and thus biocompatible capsules will be fabricated. Irradiated by near infrared light, the gold nanoparticles will heat biological macromolecules, whose conformation will consequently be changed; thus the permeability of the capsules will be increased, enabling the remote control of the drug release. A comparative study between near-infrared light, temperature and salinity on the dynamics of controlled drug release will also be carried out. Other monodisperse micro-/nano-particles will also be selected instead of the GO sheets in cores, for demonstrating the distinguished characteristics of monodisperse GO sheets regarding to drugs loading, synergistic interaction and controlled release. Based on the molecular assembly, this project will provide the essentially important theoretical and experimental guidance for the application of GO-based controlled release systems in pharmaceutics.

薄层氧化石墨烯(graphene oxide, GO) 微纳米片具有仅几个碳原子层厚的平面结构，可通过π-π电子堆积等作用吸附装载疏水药物，GO表面电荷的斥力使GO微纳米片彼此分离，提高其负载的疏水药物的水溶性。然而相对于其它微纳米粒子而言，GO在载药及药物控释方面是否具有独特优异性能是亟待解决的关键科学问题。本项目将制备3-6种2μm-50nm范围内的单分散GO，分别在单分散GO和多分散GO表面吸附疏水药物后作为内核，通过层层自组装包覆不同取代基的壳聚糖/海藻酸钠生物大分子壳层和纳米金壳层，得到含GO-药物的生物兼容胶囊；通过纳米金吸收近红外光发热诱导生物大分子构象变化提高壁层通透性，实现药物的远程控释；比较研究近红外光远程控释药物与温度或盐浓度控释药物动力学的异同；在内核中以其它单分散微纳米粒子取代单分散GO组装生物兼容胶囊，比较研究单分散GO在载药、药物协同作用及控释方面的特性。

本课题针对小尺寸氧化石墨烯(graphene oxide，GO)纳米片难以作为胶囊模板、超小GO难以制备纯化，以及如何利用GO提高含多巴胺（dopamine, DA）等痕量生物分子的多组分电催化同步检测性能、获得高表面晶胞（MnO2、Pt）利用率的催化材料等问题开展工作。首先攻克小尺寸GO纳米片极易被大分子桥联聚集的严峻问题，结合双电层原理提出了利用短链分子及通过加入适量盐提高分子链柔性作为有效解决方案的机理，为制备GO作模板的纳米胶囊提供了保障。以负载疏水药物紫杉醇（paclitaxel, PTX）的GO为内核模板、在壁内组装金纳米粒子，实现了药物的储存稳定性和在中性pH值下通过近红外光远程辐照4 min内达到突释平衡；优于文献中GO负载的药物只能在低pH =2时 (而癌细胞的pH为5.6 - 7.6)才能释放的结果。用高碘酸法得到横向尺寸20-40 nm的超小GO，探讨了渗析作为纯化的依据和关键技术细节，研究了超小GO的荧光及pH响应机理。以横向尺寸30-500 nm的GO为模板、利用GO被KMnO4氧化产生的CO2等产物鼓胀KMnO4的还原产物MnO2，并以快速冷冻干燥得到了具有大比表面（228.2 m2/g）的、直径为30-500 nm的超薄MnO2纳米空心球，厚仅3.7 nm的球壁由5层δ-MnO2晶型的[MnO6]晶胞组成，界面晶胞利用率高，催化降解有机物的单位降解量15倍于文献报道的最大值。以DA和不同尺寸GO作为前驱体，调控了氮掺杂石墨烯气凝胶(nitrogen-doped graphene aerogels，NGAs) 的孔径和比表面，提出了由小尺寸GO形成的致密小孔结构是实现低检测限、宽线性范围电催化同步检测包括痕量DA生物分子多组分的关键因素。通过小孔NGA诱导产生并负载了具有优势暴露(111)晶面的、抗毒性超薄Pt纳米片，其表面Pt原子比高达28%，故高效电催化氧化甲醇。本课题既有助于深入了解不同尺寸GO的制备纯化和基本属性，也可促进利用GO研发可控组装体系、高性能药物载体和催化剂。