Lipid nanovehicles with adjustable surface properties for overcoming multiple barriers simultaneously in oral administration

Abstract

Lipid nanoparticles (LNs) are widely investigated for oral drug delivery, and for achieving significant advantages in colloidal stability, biocompatibility and scaled-up possibility. However, researchers face challenge of developing methods to improve the ability of LNs in overcoming multiple barriers (i.e., mucus and epithelium barrier) in gastrointestinal (GI) tract because of the contradictory requirement of nanoparticle (NP) surface properties in the two processes. Therefore, we designed novel LNs with adjustable surface properties by coating lipid core with hydrophobic substitutes grafting N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA). In the present study, different substitutes (i.e., monocyclic, polycyclic, and linear segments) were grafted on pHPMA backbone. Screening studies demonstrated that type and grafting degree of substitutes both influenced hydrophilic-hydrophobic properties of NP surface and improved penetration through mucus. When a hydrophilic-hydrophobic balance was achieved, NPs showed elevated mucus permeability compared with bare LNs; this phenomenon subsequently contributed to higher cellular uptake. Moreover, β-sitosterol (SITO)-modified pHPMA-coated (grafting degree: 5%) LNs (5% SITO-LNs) exhibited the highest mucus permeability, transepithelial transport, and in situ absorption. Interestingly, even with the highest surface hydrophilicity, 5% SITO-LNs with Caco-2 cells did not show impaired membrane affinity, which was not observed in other groups. Further investigations of mechanism demonstrated that membrane affinity was significantly enhanced by β-SITO-mediated interaction with Niemann-Pick C1-like 1 (NPC1L1) protein on cell membranes. These results proved that hydrophobic substitutes play a critical role in altering hydrophilic-hydrophobic property of particle surface and improving penetration through multiple barriers. β-SITO-induced specific interaction can provide additional benefits to efficiency of oral delivery of LNs.

Transport Mechanisms of Butyrate Modified Nanoparticles: Insight into “Easy Entry, Hard Transcytosis” of Active Targeting System in Oral Administration

“…Hydrophobic interaction between NPs and hydrophobic groups on mucin could induce unwanted entrapment in mucus. Previous studies have demonstrated the importance of hydrophilic/hydrophobic balance in simultaneously penetrating the mucus layer and entering the epithelium. , Consequently, taking the basal exocytosis into consideration, we may need to find a “triple balance” upon surface hydrophobicity for the maximum mucus-penetration, endocytosis, and transcytosis. Apart from hydrophobicity, some other surface properties may also affect NP exocytosis.…”

“…16 For dye release evaluation, PBS (pH 5.0 or 7.4) were selected as release medium. In brief, 1 mL of NP suspension was sealed in a dialysis bag (MWCO: 100 kDa) and released against 40 mL of release medium for 24 h. 17 At determined time points, an aliquot of exterior medium (50 μL) was withdrawn and measured via Varioskan Flash Multimode Reader. The accumulative amount of released dye was then calculated.…”

Virus-Mimicking Mesoporous Silica Nanoparticles with an Electrically Neutral and Hydrophilic Surface to Improve the Oral Absorption of Insulin by Breaking Through Dual Barriers of the Mucus Layer and the Intestinal Epithelium

“…How the functional groups on the surface affected the hydrophilicity of MSNs was also further investigated. Since viruses possess a hydrophilic surface, the more hydrophilic the surface of MSNs, the better mimicking the virus, to enhance the oral absorption of MSNs . According to the report, the prepared nanoparticle suspensions with different concentrations were mixed with an equal volume of CBB (0.1 mM).…”

Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates

“…To investigate the mechanism of cellular internalization of OA-CAT3-SLN, various specific endocytic inhibitors were evaluated in the uptake study. Chlorpromazine (10 µg/mL) was used as the clathrin-mediated endocytic inhibitor, nystatin (5 µg/mL) as the caveolae structure and function abolisher, and methyl-β-Cyclodextrin (MCYP, 13 mg/mL) as the disruptor of lipid rafts [35][36][37]. The inhibitors were added to the cell monolayer and pre-treated for 30 min before the test.…”