药物纳米多晶型的制备及其理化、生化特异性的研究

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.

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。

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。本项目以典型的抗癌药物喜树碱及其系列衍生物为模型物，采用超临界溶析技术，结合实验、表征和分子动力学模拟，制备其纳米多晶型，研究了纳米多晶型在晶胞结构、形貌及理化性质的差异，探索了药物分子在超临界流场中多晶型成核及生长的调控规律；发明了超声辅助反溶剂膜渗析颗粒制备技术，结合超临界溶析技术，制备了若干纳米药物新剂型，详细考察了制备过程对纳米药物微结构和性能的影响，结合体外、细胞和动物实验，详细探讨了多晶型、剂型对纳米药物药理、毒理、体内传递等的影响。.本项目进展良好，已按计划完成各项任务：（1）完成论文21篇，其中在Nanomedicine: NBM、Chem. Eng. J.、Chem. Eng. Sci.、Ind. Eng. Chem. Res.、化工学报等国内外重要刊物发表（录用）16篇（SCI 收录11篇、EI 收录3篇），国际会议论文3篇，国内会议主题报告1篇，另有1篇论文投稿AIChE J.审稿中；（2）申请中国发明专利6件，其中2件已获授权；（3）培养博士后1名、博士生2名、硕士生11名，其中1名博士生获得国家留学基金，赴英国伯明翰大学联合培养；1名博士生毕业后进入上市公司康芝药业博士后工作站，合作推进相关成果的产业化。.上述成果的详细创新请参见报告正文，研究结果可为药物纳米多晶型、纳米新剂型的研究和应用提供很好的基础数据和理论支撑。在国家自然科学基金的持续支持下，项目组在超临界溶析（SAS）技术制备纳米药物方面取得可喜进展，形成了基础研究与工程应用并重的特色，项目组受邀为国际知名刊物Current Pharmaceutical Design撰写的长篇评述性论文“Tailoring Particle Microstructures via Supercritical CO2 Processes for Particular Drug Delivery”于2015年刊出，引起学术和企业届的关注。