Pure drug nanoparticles (NPs) represent a promising formulation for improved drug solubility and controlled dissolution velocity. However, limited absorption by the intestinal epithelium remains challenge to their clinical application, and little is known about how these NPs within the cells are transported. To improve cellular uptake and transport of pure nanodrug in cells, here, a lipid covered saquinavir (SQV) pure drug NP ([email protected]) was designed by modifying a pure SQV NP (nanodrug) with a phospholipid bilayer. We studied their endocytosis, intracellular trafficking mechanism using Caco-2 cell model. Uptake of [email protected] by Caco-2 cells was 1.91-fold greater than that of pure nanodrug via processes involving cell lipid raft. The transcellular transport of [email protected] across Caco-2 monolayers was 3.75-fold and 1.92-fold higher than that of coarse crystals and pure nanodrug, respectively. Within cells, [email protected] was mainly localized in the endoplasmic reticulum and Golgi apparatus, leading to transcytosis of [email protected] across intestinal epithelial cells, whereas pure nanodrug tended to be retained and to dissolve in cell and removed by P-gp–mediated efflux. In rats, the oral bioavailability of the model drug SQV after [email protected] administration was 4.29-fold and 1.77-fold greater than after coarse crystal and pure nanodrug administration, respectively. In conclusion, addition of a phospholipid bilayer to pure drug NP increased their cellular uptake and altered their intracellular processing, helping to improve drug transport across intestinal epithelium. To our knowledge, this is the first presentation of the novel phospholipid bilayer covered SQV pure drug NP design, and a mechanistic study on intracellular trafficking in in vitro cell models has been described. The findings provide a new platform for oral delivery of poorly water-soluble drugs.

纯药物纳米颗粒（NPs）代表了一种有望改善药物溶解度和控制溶出速度的配方。然而，肠上皮的有限吸收仍然是对其临床应用的挑战，并且关于细胞内这些NP如何运输的知之甚少。为了提高细胞对纯纳米药物的摄取和转运，在这里，通过用磷脂双层修饰纯SQV NP（纳米药物）来设计脂质覆盖的沙奎那韦（SQV）纯药物NP（[电子邮件保护]）。我们使用Caco-2细胞模型研究了它们的内吞作用，细胞内运输机制。通过涉及细胞脂质筏的过程，Caco-2细胞对[电子邮件保护的]的吸收比纯纳米药物的吸收高1.91倍。[电子邮件保护的]跨Caco-2单层的跨细胞运输是3.75倍和1。分别比粗晶体和纯纳米药物高92倍。在细胞内，[受电子邮件保护的]主要位于内质网和高尔基体中，从而导致[受电子邮件保护的]跨小肠上皮细胞的胞吞作用，而纯纳米药物倾向于保留并溶解在细胞中，并被P-gp去除。介导的外排。在大鼠中，模型药物SQV在[电子邮件保护]后的口服生物利用度分别比粗晶和纯纳米药物后的口服生物利用度分别高4.29倍和1.77倍。总之，在纯药物NP中添加磷脂双层可增加其细胞摄取并改变其细胞内加工过程，从而有助于改善药物跨肠上皮的运输。据我们所知，已经描述了体外细胞模型。这些发现为水溶性差的药物的口服给药提供了新的平台。