Zhang Jifen, Corpstein Clairissa D, Li Tonglei
College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China.
Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 47907, USA.
Acta Pharm Sin B. 2021 Apr;11(4):1021-1029. doi: 10.1016/j.apsb.2020.09.017. Epub 2020 Oct 14.
Nanocrystal formulations have been explored to deliver poorly water-soluble drug molecules. Despite various studies of nanocrystal formulation and delivery, much more understanding needs to be gained into absorption mechanisms and kinetics of drug nanocrystals at various levels, ranging from cells to tissues and to the whole body. In this study, nanocrystals of tetrakis (4-hydroxyphenyl) ethylene (THPE) with an aggregation-induced emission (AIE) property was used as a model to explore intracellular absorption mechanism and dissolution kinetics of nanocrystals. Cellular uptake studies were conducted with KB cells and characterized by confocal microscopy, flow cytometry, and quantitative analyses. The results suggested that THPE nanocrystals could be taken up by KB cells directly, as well as in the form of dissolved molecules. The cellular uptake was found to be concentration- and time-dependent. In addition, the intracellular THPE also could be exocytosed from cells in forms of dissolved molecules and nanocrystals. Kinetic modeling was conducted to further understand the cellular mechanism of THPE nanocrystals based on first-order ordinary differential equations (ODEs). By fitting the kinetic model against experimental measurements, it was found that the initial nanocrystal concentration had a great influence on the dynamic process of dissolution, cellular uptake, and exocytosis of THPE nanocrystals. As the nanocrystal concentration increased in the culture media, dissolution of endocytosed nanocrystals became enhanced, subsequently driving the efflux of THPE molecules from cells.
人们已探索使用纳米晶体制剂来递送水溶性差的药物分子。尽管对纳米晶体制剂和递送进行了各种研究，但在从细胞到组织再到全身的各个层面，仍需要对药物纳米晶体的吸收机制和动力学有更深入的了解。在本研究中，以具有聚集诱导发光（AIE）特性的四（4-羟基苯基）乙烯（THPE）纳米晶体为模型，探讨纳米晶体的细胞内吸收机制和溶解动力学。用KB细胞进行细胞摄取研究，并通过共聚焦显微镜、流式细胞术和定量分析进行表征。结果表明，THPE纳米晶体可以直接被KB细胞摄取，也可以以溶解分子的形式被摄取。发现细胞摄取具有浓度和时间依赖性。此外，细胞内的THPE也可以以溶解分子和纳米晶体的形式从细胞中胞吐出来。基于一阶常微分方程（ODEs）进行动力学建模，以进一步了解THPE纳米晶体的细胞机制。通过将动力学模型与实验测量值进行拟合，发现初始纳米晶体浓度对THPE纳米晶体的溶解、细胞摄取和胞吐的动态过程有很大影响。随着培养基中纳米晶体浓度的增加，内吞纳米晶体的溶解增强，随后驱动THPE分子从细胞中流出。
