“壳-核”型纳米粒的“壳”组成对克服口服生理屏障及生物利用度的影响

Effects of shell composition in shell-core structured nanoparticles on oral physiological barrier and bioavailability

基于克服胃肠道黏液及肠上皮细胞生理屏障,分别以混合脂质(Lipoid S100与DSPE-PEG 2000)和聚合物F127为壳,以PLGA为核制备“壳-核”型纳米粒,研究不同类型的壳组成对克服口服生理屏障及生物利用度的影响,为提高中药口服纳米载体生物利用度的研究提供一定的依据和借鉴。以水飞蓟宾(silibinin,SLB)为模型药物,采用改良的纳米沉淀法分别制备以混合脂质为壳、PLGA为核的纳米粒(SLB-LPNs)与以F127为壳、PLGA为核的纳米粒(SLB-FPNs)。透射电镜显示LPNs与FPNs均呈球形,具有壳核结构。SLB-LPNs与SLB-FPNs的平均粒径分别为(94.13±2.23)、(95.42±4.91)nm,Zeta电位分别为(-39.3±2.8)、(-17.0±0.2)mV。XRD分析表明SLB均以分子或无定形状态存在于2种纳米粒中。通过细胞内化动力学考察并分析纳米粒穿越黏液层和细胞摄取的综合能力,与FPNs相比,LPNs在同一时间细胞内累积的量更多,表明LPNs可以更快速地穿越黏液层并被细胞内化。以SLB混悬剂为参比制剂,研究了纳米粒大鼠体内药代动力学。与参比制剂相比,SLB-LPNs与SLB-FPNs的相对生物利用度分别为400.37%和923.31%。研究表明,不同壳组成对纳米粒克服黏液层及肠上皮细胞生理屏障和口服生物利用度有一定的影响,壳-核结构纳米粒作为口服纳米载体具有良好的发展前景。

The present study prepared shell-core nanoparticles comprising poly(lactic-co-glycolic acid)(PLGA)cores encapsulated by shells composed of mixed lipids(Lipoid S100 and DSPE-PEG 2000)or polymer F127 to investigate the effects of shell composition on overcoming physiological barriers of gastrointestinal mucus and intestinal epithelial cells and improving bioavailability.The results are expected to provide references for the research on the improvement of the oral bioavailability of Chinese medicine by nanocar-riers.Silibinin(SLB)was used as a model drug to prepare PLGA nanoparticles coated with the shell of mixed lipids(SLB-LPNs)or F127(SLB-FPNs)via a modified nanoprecipitation method.Transmission electron microscopy showed that both LPNs and FPNs were spherical with a core-shell structure.The average particle sizes of SLB-LPNs and SLB-FPNs were(94.13±2.23)and(95.42±4.91)nm,respectively.The Zeta potential values were(-39.3±2.8)and(-17.0±0.2)mV,respectively.X-ray diffraction analysis revealed the presence of SLB in the two types of nanoparticles in a molecular or amorphous state.The ability of nanoparticles to cross both the mucus and epithelial barriers were evaluated using the cellular internalization kinetics assay.LPNs showed a higher rate of cell internalization than FPNs,indicating that LPNs could penetrate the mucus layer and become internalized by cells more rapidly.As revealed by the in vivo pharmacokinetic assay in rats with SLB suspension as the reference,the relative oral bioavailability of SLB-LPNs and SLB-FPNs was 400.37%and 923.31%,respectively.The effect of SLB-FPNs in improving oral bioavailability was more significant than that of SLB-LPNs.In summary,shell composition can influence the ability of nanoparticles to overcome oral physiological bar-riers,such as the mucus layer and intestinal epithelial cells,and improve oral bioavailability.Shell-core structured nanoparticles are promising nanocarriers for oral drug delivery systems.