title: Mechanism of transport of saquinavir-loaded nanostructured lipid carriers across the intestinal barrier.
abstract: The aims of this work were (i) to evaluate the potential of nanostructured lipid carriers (NLCs) as a tool to enhance the oral bioavailability of poorly soluble compounds using saquinavir (SQV), a BCS class IV drug and P-gp substrate as a model drug, and (ii) to study NLC transport mechanisms across the intestinal barrier. Three different NLC formulations were evaluated. SQV transport across Caco-2 monolayers was enhanced up to 3.5-fold by NLCs compared to SQV suspension. M cells did not enhance the transport of NLCs loaded with SQV. The size and amount of surfactant in the NLCs influenced SQV's permeability, the transcytosis pathway and the efflux of SQV by P-gp. An NLC of size 247 nm and 1.5% (w/v) surfactant content circumvented P-gp efflux and used both caveolae- and clathrin-mediated transcytosis, in contrast to the other NLC formulations, which used only caveolae-mediated transcytosis. By modifying critical physicochemical parameters of the NLC formulation, we were thus able to overcome the P-gp drug efflux and alter the transcytosis mechanism of the nanoparticles. These findings support the use of NLCs approaches for oral delivery of poorly water-soluble P-gp substrates.
authors.affiliation: Pharmacokinetics, Nanotechnology and Gene Therapy Group, Laboratory of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Beloqui
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: Solinís
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Gascón
authors.forename: Ana
authors.initials: A
authors.lastname: del Pozo-Rodríguez
authors.forename: Anne
authors.initials: A
authors.lastname: des Rieux
authors.forename: Véronique
authors.initials: V
authors.lastname: Préat
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D004337:Drug Carriers; D004339:Drug Compounding; D004705:Endocytosis / Q000187:drug effects; D020895:Enterocytes; D006801:Humans; D007408:Intestinal Absorption; D008055:Lipids / Q000737:chemistry*; D053758:Nanoparticles; D010316:Particle Size; D019258:Saquinavir / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013501:Surface-Active Agents; D013535:Suspensions; D057900:Transcytosis
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D004337:Drug Carriers; D008055:Lipids; D013501:Surface-Active Agents; D013535:Suspensions; D019258:Saquinavir