药物纳米多晶型的制备及其理化、生化特异性的研究

多晶型是关键的药物质量指标，通过药物超细化并调控其多晶型，可显著提高药物的溶解速率和生物利用度。但在药物纳米多晶型的制备、调控及性能测试等方面仍有待进一步研究。本项目拟以典型的抗癌药物紫杉醇、喜树碱及其系列衍生物为模型物，采用超临界溶析技术结合在线检测，制备其纳米多晶型，研究纳米多晶型在晶胞结构、形貌及理化性质的差异，结合实验、表征和分子动力学模拟，探索有机药物分子在超临界流场中多晶型成核及生长的调控规律；将纳米多晶型分散于生理盐水中形成稳定微分散体系，采用Plexarray HT高通量生化过程分析系统研究纳米药物-蛋白靶标亲和力、作用动力学及体内传递特异性，探讨粒径及分布、多晶型对纳米药物-蛋白靶标作用效果的影响，建立相应的纳米药物-蛋白靶标作用机理模型。本项目具有很好的前瞻性和创新性，预期研究结果将为药物纳米多晶型的研究和应用提供很好的理论和基础数据支撑。

Polymorphism is the key property of pharmaceuticals, solubility and bioavailability of pharmaceuticals can be greatly improved by nanocrystallization and control of its polymorph. However, the emerging field of nanomedicine faces several challenges including the general complexity of biological systems interacting with nanoscale materials and devices, the translation of novel measurement concepts and methods into daily clinical routine, and concerns about the safety, potential toxicity, and efficacy of nanoscale medical devices, diagnostic techniques, and materials. In this proposal, typical anti-cancer medicines, i.e., paclitaxel, camptothecin and their ramifications, are selected as model pharmaceuticals, and the supercritical anti-solvent crystallization coupled with on line measurements is adopted to nanocrystillize the model pharmaceuticals. The difference of crystal structure, morphology and physical and chemical properties will be studied for identifying the nanocrystals. The transformation rule and regulative method of polymorph for SAS process will be emphasized by combining methods of experiment, analysis and molecular dynamics simulation. The samples of nanocrystals will be dispersed into normal saline to prepare stable nanomedicine, and Plexarray high throughput biochemical screening system is selected to analyze thousands of interactions in parallel between nanocrystal and protein. The effect of particle size and its distribution, polymorphism on the efficiency of nanomedicine to target will be demonstrated, and the mechanism for interaction between nanomedicine and target will be put forward and validated. The results are promising for the enhancement of fundamental and application of nanomedicine.