Abstract

Nanotechniques show significant merits in terms of improving the oral bioavailability of poorly water-soluble drugs. However, the mechanisms behind are not clear yet. For instance, what is the contribution of free drug released during nanogranule transcytosis , as well as the impact of drug transporter and chylomicron ? To address these issues, sorafenib nanogranules (SFN-NGs) were prepared as model by the high-gravity antisolvent precipitation method which approaches to practical mass production. Then, a multiaspect study on the transcytosis mechanism of SFN-NGs was conducted in Caco-2 cells and rats, including paracellular transport , endocytosis, intracellular trafficking, transmembrane pathway, as well as the involvement of transporter and chylomicron. Pharmacokinetics in rats demonstrated an obvious superiority of SFN-NGs in oral absorption and lymphatic transfer over SFN crude drugs . Different from free SFN, SFN-NGs could be internalized in cells in early stage by caveolin/lipid raft or clathrin induced endocytosis, and transported intactly through the polarized cell monolayers. While in late stage, transporter-mediated transport of free SFN began to play a vital role on the transmembrane of SFN-NGs. No paracellular transport of SFN-NGs was found, and the trafficking of SFN-NGs was affected by the pathway of ER-Golgi complexes. Surprisedly, the intracellular free SFN was the main source of transmembrane for SFN-NGs, which was entrapped into chylomicrons and then secreted into the extracellular space. Generally, the findings in current study may shed light on the absorption mechanism of oral nanoformulations.