基于高分辨X射线显微成像研究缓控释药物载体PLGA微球的降解过程及配方优化

In recent years, with the rapid advances in genetic engineering, recombinant technology and proteomics, many new peptides and protein-based drugs play an important role in treatment, diagnosis and prevention of many disease using vaccines. The development of controlled-release drug mechanisms is an important route to minimize side effects and increase the tolerability of patients. .By using polylactic acid (eg: PLGA etc.), a biodegradable polymers, biological macromolecules drug are enveloped into sustain controlled release intramuscular injection microspheres, improve the bioavailability of the drugs, and achieve controlled or sustained release. Due to the absence of extensive theoretical support of preparation on prescription factors, physical and chemical properties of the microspheres and drug release properties of microspheres, the PLGA microspheres carried protein drugs research is low efficiency, hard to success and has a long development period..By simulating the release environment of protein drugs carried in PLGA microspheres in vitro, establishing the microspheres release models, combining the high-resolution X-ray microscopy which can observe the internal structure of the sample at high resolution without damage, this project can research three-dimensional distribution of the microspheres skeleton and drugs in space and time, and have the utmost significance and research prospects in the establishment and development of mathematical modeling of drug release, shortening the microspheres development period and improving the efficiency of research and development.

近些年来，伴随着基因工程重组技术和蛋白组学的飞速进步，许多新型多肽、蛋白类药物在治疗、诊断和疫苗预防疾病方面发挥着重要的作用。发展多肽、蛋白类药物的缓控释制剂是解决长时间用药、药物毒副作用及耐受性的关键。.利用聚乳酸类（如：PLGA等）生物可降解聚合物，将生物大分子药物包被成缓控释肌注微球可提高药物的生物利用度，实现药物控释或缓释。但是目前缺乏关于微球制备工艺、处方因素、微球理化性质及释药性能之间广泛深入的理论支持，导致了负载蛋白质类药物的PLGA微球科研效率低、周期长，成功率低。.本项目通过模拟蛋白质类药物在PLGA微球体外释放环境，建立微球体外释放模型，结合能够在高分辨率下无损观测样品内部结构的X射线高分辨显微成像技术，可以研究微球骨架及药物在空间及时间上的三维分布，对药物释放数学模型建立及发展，建立高效的筛选平台，缩短微球研发周期，提高研发效率有极为重大的意义及研究前景。

随着生物制药技术和蛋白质组学的快速发展，众多蛋白质类药物在疾病的诊治和预防中发挥着越来越重要的作用，但是目前蛋白质类药物载体的结构研究仍很缓慢。本项目利用北京同步辐射装置和国家同步辐射实验室开展了PLGA微球的高分辨X射线成像实验，筛选出了微球样品的最佳处理方法，完成了硬X射线成像实验三维重建数据进行分割渲染的程序优化，并获得了足以区分微球外表面、微球骨架、微球内部孔隙和蛋白质类药物的结构参数。. 在X射线光栅相位衬度成像方法的研究中，使用常规实验室X射线光源对新鲜的樱桃番茄和干酸梅进行了Talbot-Lau干涉成像实验，提取了X射线吸收、折射、散射信息，综合利用这三种图像衬度信息，可清晰分辨样品各区域的内部结构，相关研究成果发表于Nuclear Science and Techniques, 2017.2, 28(2): 0~24。. 同时，在X射线成像新技术新方法的研究中，我们发展了一种利用X射线泽尼克相位衬度成像技术来进行元素分辨的方法，相关研究成果发表于Chinese Physics B, 2016.10, 25(10): 0~10870；开展了单次曝光硬X射线光栅干涉仪成像新方法的研究，相关研究成果发表于Journal of Synchrotron Radiation, 2019.1, 26(1):215~219；获得了X射线衍射增强成像中的信息提取的新方法，相关研究成果发表于Journal of Synchrotron Radiation, 2018.7, 25(4): 1206~1213。.