基于分子影像技术活体研究转铁蛋白受体介导的类脂质体药物脑内递药特性

Cerebrovascular disease and central nervous system disease are threatening human health and the quality of life. However, the delivery of therapeutic agents for brain diseases is far from efficient due to the blood-brain barrier, so it becomes hotspot. In order to improve drug targeting index, our study will use various technologies to evaluate the effectiveness of a new type of therapeutic agent, in which ginkgolide and memantine hydrochloride, as the potential therapeutic agent, will be encased into a new nonionic surfactant vesicle conjugated with transferrin receptor monoclonal antibody OX26. In this research, we will use pharmacy techniques, cell engineering and molecular imaging techniques et al to test the physicochemical property of this new type of drug carriers, including its characteristics of potential clinical drug; the vitro BBB cell models are established in order to investigate the mechanism of cellular uptake and transport for 0X26-NSV; use positron emission tomography （PET）techniques to inspect the biodistribution of the drug in the normal brain, determine its pharmacodynamic parameters in vivo, explore the mechanism of drug action at the molecular level; use rat model of Parkinson's Disease (PD) and single photon emission computed tomography (SPECT), to investigate the neuroprotective effects of 0X26-NSV on substantia nigna neurons, and use PET FDG imaging to observe glucose metabolic changes during treatment in different domains of the brain, and to analyze the relationship between drug distribution and alterations in brain function. In summary, our study will investigate the usefulness of this new type of therapeutic agent for brain disease, providing important preclinical data for the future development of targeted therapy for brain diseases, paving the way for the potential clinical translation of this new therapeutic agent, which are all of great academic and social importance.

脑血管和神经性功能病变是威胁人类健康和生活质量的主要疾病。血脑屏障的存在严重影响许多药物在脑内的分布及疗效，使"增强药物突破血脑屏障能力"成为研究热点。本项目以提高药物脑靶向指数为目标，制备一种转铁蛋白受体单克隆抗体介导的类脂质体来包装治疗性药物银杏内酯和盐酸美金刚，运用药剂学、细胞工程及分子影像等手段，研究该脑靶向制剂的理化特性及潜在临床应用前景。建立体外血脑屏障细胞模型，解析其通过细胞跨膜转运、摄取机制；运用PET技术，考察药物在正常脑内的分布，测定药物在生物体内的药效学参数，从分子水平探究药物作用机制；建立大鼠帕金森模型，运用SPECT显影评价药物对大鼠的脑神经保护作用；利用PET的FDG糖代谢功能显像，观察药物对脑内不同域的代谢变化，分析药物分布与脑功能改变之间的关系，为药物的潜在临床转化能力提供准确的前期数据。该研究将为脑靶向性药物研发奠定科学理论基础，具有重要的学术和社会意义。

本项目以提高药物脑靶向指数为目标，制备一种转铁蛋白受体单克隆抗体介导的类脂质体来包装治疗性药物银杏内酯，运用药剂学、细胞工程及分子影像手段等，研究该脑靶向制剂的理化特性及潜在临床应用前景。0X26-NSV平均粒径为185.9 ± 52.5 nm，优化配方的Zeta电位为−19.8 ± 1.3 mV。银杏内酯B脂微球在室温下能保存至少三个月。对大鼠做单次4 mg/kg的静脉注射后，通过药代动力学数据分析与统计分析，得到了CL(L/h)清除率：2.594，Cmax (ng•mL-1)：353.8，T1/2(h)：1.044。脑组织分布研究结果 ：给药后0.5h脑组织中银杏内酯B的浓度即达到峰值，2小时后脑组织中银杏内酯B的浓度显著下降。银杏内酯B脂微球的AUC比银杏内酯B注射液的高出大约1.57倍。与市售相关药物制剂相比，延长药物在脑内滞留时间，从而提高药物对脑部病变的治疗指数为目标；类脂质体药物被单核巨噬细胞吞噬系统吞噬，即刻从血液中清除，因而造成血脑屏障。类脂质体的表面特性如亲水亲脂性强弱、表面电位，与转铁蛋白在其表面的吸附性能息息相关。一般来说类脂质体的表面亲脂性越强、表面电位越低，转铁蛋白容易吸附。转铁蛋白类脂质体在体外 BBB 模型的转运行为研究表明，X26-NSV转运是通过细胞内吞的被动扩散的方式进行，该研究将为脑靶向性药物研发奠定科学理论基础，具有重要的学术和社会意义。