A multiaspect study on transcytosis mechanism of sorafenib nanogranules engineered by high-gravity antisolvent precipitation

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.