利用活体动物模型研究代表性纳米载体对血-脑脊液屏障的生物效应

Central nervous system disease is a kind of disease that seriously challenging human health. Traditional treatments for such disease include intracranial administration, transient blood-brain barrier damage, implantation of sustained-released polymeric film etc. Till now, there is still no effective way for the complete cure and eradication of central nervous system disease. This is mainly due to the limitation of current therapeutic technique and blood-brain barrier. The application of nanotechnology for drug delivery is widely expected to bring new hope for non-invasive brain administration. However, whether nanocarriers could penetrate through the blood-brain barrier or not is still very controversial and lack of convincing experimental evidence that is generally accepted by the basic and clinic data. Hence, it is very urgent and essential to study the permeability of nanocarriers on the central nervous system. In our project, we choose gold nanoparticles, which have multiple appealing advantages including controlled particle size distribution, good biocompatibility, and easy of detection, as the representative nanocarrier model; and rats that could be intravenously injected with nanocarriers and from which cerebrospinal fluid could be continuously obtained as live animal model. Blood-cerebrospinal fluid barrier is also used as a representative model of the barrier of central nervous system. Using these models, we would like to systematically study the influence of size distribution and surface modification on the permeability of nanocarriers across blood-cerebrospinal fluid barrier and their unique biological effects in vivo. By virtue of the mechanism by which nanocarriers pass across blood-cerebrospinal fluid barrier, together with rat model of meningitis established based on staphylococcus aureus infection, we wish to further evaluate the effectiveness of optimized nanocarriers in clinical animal models of brain disease. By exploring the permeability of nanocarriers across blood-cerebrospinal fluid barrier and their unique biological effects in live rat models, the present project will provide scientific basis for the future treatment regimen of central nervous system disease. Moreover, clarifying the key factors related to permeability of nanocarriers across blood-cerebrospinal fluid barrier through multidisciplinary will undoubtedly provide an important guidance for revealing their mechanism and clinical application. By means of promoting the multidisciplinary and integration of nanoscience, materials science, medicine etc., we expect to establish anddevelop new models to improve the therapeutic effect of critical diseases of thebrain using nanotechnology.

中枢神经系统疾病是严重危害人类生命健康的疾病，且迄今尚缺乏有效治疗手段。纳米载体的高效输运为脑部非侵入性药物递送提供了可能，但是纳米载体通透血脑屏障的研究因缺乏有力证据而存在争议。针对纳米载体相关特性对其穿透屏障能力和生物效应的影响仍缺乏系统的研究。本项目选择粒径等理化特性可控，生物兼容性好，便于检测的金纳米颗粒为核心且表面经不同修饰的载体为代表性纳米结构，采用可连续获取脑脊液的大鼠为动物模型，以其血脑脊液屏障作为典型中枢神经系统屏障，研究纳米载体不同特征与其对血脑脊液屏障生物效应的关系。建立细菌感染的大鼠脑膜炎模型，研究纳米载体输运庆大霉素的血脑屏障通透能力。本项目通过在活体动物体内探索纳米载体透过血脑脊液屏障的生物效应，阐明决定纳米载体透过血脑屏障的关键因素及其相互作用机制和规律，为中枢神经系统药物递送纳米载体的优化设计和选择提供切实可靠的研究依据，为改善脑部疾病治疗提供新研究模式。

本项目针对纳米载体相关特性对其穿透屏障能力和生物效应的影响缺乏系统研究的关键科学问题，构建一系列具有良好生物相容性和稳定性的模型纳米载体（以金颗粒为核心的具有不同粒径、表面电荷、表面状态的金纳米颗粒），成功建立大鼠脑脊液实时收集动物模型。利用该模型，研究不同尺寸（15nm, 50 nm, 100 nm）对于血脑脊液屏障通透性的影响，筛选出纳米颗粒透过血脑脊液屏障的最优粒径为50 nm，并利用生物电镜技术探索纳米载体通过此屏障的可能机制，认为金纳米颗粒主要是通过纤毛进入脑脊液，从而透过血脑脊液屏障；同时开展了金纳米颗粒对脑部的生物效应基础研究，为纳米载体在脑部药物递送领域的关键技术地位提供理论基础。同时，本项目作为一个基础研究平台能够帮助解决有效但无法穿越血脑脊液屏障的药物递送问题以及为未来脑部纳米载体的成药性基础规律提供积极探索。