金属有机骨架材料缓释药物个体化设计模式构建及作用机制研究

The choice of carrier materials is a critical point for the researches of sustained release medication. However, the chemical structure diversity of drugs and the fixity of carrier materials lead to the random selection problem for delivery materials. If a carrier material could have the properties of high drug-loading amount and sustained releasing the embedded drug, and could automatically regulate structure according to the drug characteristics, it would benefit to scientific researches of sustained release preparations. Metal organic frameworks (MOFs) are an ideal carrier material due to its high aperture ratio and aperture-ligand bidirectional regulation, which also provides the feasibility for personalized design. The project aims to design sustained releasing MOFs which could embed/load massive different structural oridonin and curcumin, and could slowly release them; our research intends to build a personalized designed mode for drug release to adjust MOFs’ apertures and organic ligands on the basis of drug chemical structures and properties, which helps to deeply investigate the releasing rules and mechanisms. This research plays an important role in studying sustained and controlled release medication. It enables to improve the releasing rate of several drugs with short half-life period, low bioavailability and the requirement of sustained release.

载体材料的选择是药物缓释制剂研究的关键，但由于药物性质结构的多样性、载体材料结构的固定性，在为药物寻找适合的缓释材料时会有一定的的盲目性和随机性，如果有一种可以根据药物性质方便地进行结构调整，达到高载药量、缓慢释药的载体材料将会更好地适合缓释制剂的研究。金属有机骨架材料（MOFs）由于高孔隙率、孔径-配体的双可调节性，成为一种不错的选择，也为药物缓释研究中提供了个体化设计可能性。本课题研究旨在围绕具有不同结构特点的冬凌草甲素、姜黄素进行缓释个体化设计，达到高载药量、缓慢释放的目的，构建一种药物缓释个性化设计的模式，从而可以根据药物分子的结构、性质，针对性地调整MOFs孔径、有机配体等结构，达到药物的最大载药和缓慢释药，并对其缓释作用规律和机制进行研究。为更多半衰期短、需要缓慢释放、生物利用度低的药物进行缓释改进提供研究基础，对药物缓控释制剂的研发具有重要作用。

本项目基于MOFs材料的缓释性、孔径-配体的双可调节性，制备了孔径不同、孔径相同配体不同的系列MOFs材料，围绕具有不同结构特点的中药活性成分冬凌草甲素和姜黄素进行了载药性能优选、释药规律研究和材料安全性初步评价，结果发现MOFs材料的孔径和有机配体均对载药性能有较大影响，MOFs材料孔径与药物分子尺寸接近时、有机配体与药物分子间相互作用大时载药性能最佳；MOFs材料载药后药物的释放属于一阶释药过程，以扩散作用为主；此系列MOFs材料作为药物载体具有良好的生物相容性。基于此研究结果，本项目构建了“药物分子粒径、结构分析→选择孔径接近、配体作用力强的MOFs材料→制备药物缓释粒子”的药物金属有机骨架材料个性化载药模式，能够达到高载药量、缓慢释放的目的。本项目制备的不同孔径、不同配体的九种MOFs材料，能够为金属有机骨架材料缓释药物个体化设计模式的应用提供足够的材料选择，保证其顺利应用。本项目研究成果也能够为更多半衰期短、需要缓慢释放、生物利用度低的药物进行缓释改进提供了借鉴和参考，对药物缓控释制剂的研发具有深远意义。项目研究成果发表SCI论文7篇，核心期刊论文2篇，培养硕士研究生3名。