Nanoparticles targeting the intestinal Fc receptor enhance intestinal cellular trafficking of semaglutide
Semaglutide is the first oral glucagon-like peptide-1 (GLP-1) analog commercially available for the treatment of type 2 diabetes. In this work, semaglutide was incorporated into poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NPs) to improve its delivery across the intestinal barrier. The nanocarriers were surface-decorated with either a peptide or an affibody that target the human neonatal Fc receptor (hFcRn), located on the luminal cell surface of the enterocytes.
Highlights
- Semaglutide was successfully incorporated into FcRn-targeted polymeric nanoparticles.
- FcRn-targeted nanoparticles bound to hFcRn in a pH-dependent manner, with a stronger interaction at pH 6 than at pH 7.4.
- FcRn-targeted nanoparticles showed higher interaction with in vitro intestinal models than non-targeted nanoparticles.
- Injection of nanomedicines into intestinal organoids’ lumen is a promising tool to evaluate cell-nanopartices interaction.
Both ligands were successfully conjugated with the PLGA-PEG via maleimide-thiol chemistry and thereafter, the functionalized polymers were used to produce semaglutide-loaded NPs. Monodisperse NPs with an average size of 170 nm, neutral surface charge and 3% of semaglutide loading were obtained. Both FcRn-targeted NPs exhibited improved interaction and association with Caco-2 cells (cells that endogenously express the hFcRn), compared to non-targeted NPs. Additionally, the uptake of FcRn-targeted NPs was also observed to occur in human intestinal organoids (HIOs) expressing hFcRn through microinjection into the lumen of HIOs, resulting in potential increase of semaglutide permeability for both ligand-functionalized nanocarriers. Herein, our study demonstrates valuable data and insights that the FcRn-targeted NPs has the capacity to promote intestinal absorption of therapeutic peptides.
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Soraia Pinto, Mahya Hosseini, Stephen T. Buckley, Wen Yin, Javad Garousi, Torbjörn Gräslund, Sven van Ijzendoorn, Hélder A. Santos, Bruno Sarmento, Nanoparticles targeting the intestinal Fc receptor enhance intestinal cellular trafficking of semaglutide, Journal of Controlled Release, Volume 366, 2024, Pages 621-636, ISSN 0168-3659,
https://doi.org/10.1016/j.jconrel.2024.01.015.