目的 基于“鼻-脑”通路体外细胞模型，探索药物制剂经鼻入脑的影响因素。方法 将Calu-3细胞与嗅神经鞘细胞（OECs）细胞共培养，构建“鼻-脑”通路细胞模型组。以荧光素异硫氰酸酯右旋葡萄糖苷（FD）和荧光纳米银粒子（AgNPs）为模型药物，探索药物相对分子质量（M_w）因素及制剂粒径因素对药物经鼻入脑的影响。结果 FD随M_w增大其跨细胞单层膜转运表观渗透系数（P_app）减小；OECs对不同M_w FD的摄取在90 min后摄取量趋于饱和，随其M_w增大，相同摄取时间OECs摄取量有明显下降趋势。不同粒径荧光AgNPs在“鼻-脑”多通路细胞模型组Calu-3单层的P_app随纳米粒的粒径增大而减小，粒径<40 nm，其在Calu-3的转运特性表现为中等吸收（1×10^-6 < P_app < 10×10^-6），粒径>60 nm，其转运特性为难吸收（P_app<1×10^-6）；OECs对不同粒径荧光AgNPs的摄取在60 min趋于饱和且随其粒径增大，相同摄取时间OECs摄取量有明显下降趋势。结论 药物M_w大小及纳米制剂的粒径对于药物经鼻转运入脑具有重要影响，M_w<4 000的药物，粒径<40 nm的纳米粒子具有更好转运和摄取特性。

Objective To explore the factors affecting the nasal entry of the pharmaceutical preparations into the brain based on the established model of the “nose-brain” pathway in vitro. Methods Calu-3 cells and OECs cells were co-cultured to construct a “nasal-brain” pathway cell model group. Taking fluorescein isothiocyanate dextran (FD) and fluorescent silver nanoparticles (AgNPs) as model drugs, the effects of drug molecular weight (M_w) factors and preparation particle size factors on the drug transnasal transport into the brain were explored. Results The apparent permeability coefficient (P_app) of transcellular monolayer transport of FD decreased with the increase of molecular weight. The uptake of fluorescein isothiocyanate dextran with different molecular weights by OECs tended to be saturated after 90 min. As the molecular weight of FD increased, the uptake of OECs decreased significantly during the same uptake time. The apparent permeability coefficient of fluorescent AgNPs with different particle sizes in the “nose-brain” multi-channel cell model group of calu-3 monolayer decreased with the increase of the particle size of the nanoparticles. When the particle size was less than 40 nm, its transport characteristics in Calu-3 were shown as medium absorption (1×10^-6 < P_app < 10×10^-6), and when the particle size of nanoparticles was more than 60 nm, its transport characteristics were shown as difficult to absorb (P_app < 1×10^-6). The uptake of OECs of fluorescent AgNPs with different particle sizes tended to be saturated at 60 min, and with the increase of the particle size of fluorescent AgNPs, the uptake of OECs at the same uptake time showed a significant decline. Conclusions The M_w of the drug and the particle size of the nano-formulation have an important influence on the nasal transport of the drug into the brain. Drugs with a molecular weight of < 4 000 and nano particles with a particle size of less than 40 nm have better transport and uptake characteristics.

R283.6

国家自然科学基金项目（81803738）；中央高校基本科研业务费专项资金资助（2020-JYB-ZDGG-034）；中央高校基本科研业务费专项资金资助（2018-JYBZZ-JS019）