Bioengineered Nanomedicines Targeting the Intestinal Fc Receptor Achieve the Improved Glucoregulatory Effect of Semaglutide in a Type 2 Diabetic Mice Model.

Autor:	Pinto S; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal.; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, Porto 4050-313, Portugal., Viegas J; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal., Cristelo C; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal.; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, Porto 4050-313, Portugal., Pacheco C; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal.; Instituto Universitário de Ciências da Saúde (IUCS-CESPU), Rua Central de Gandra 1317, Gandra 4585-116, Portugal., Barros S; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal.; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Rua Jorge de Viterbo Ferreira 228, Porto 4050-313, Portugal., Buckley ST; Global Research Technologies, Novo Nordisk, Novo Nordisk Park 1, Måløv 2760, Denmark., Garousi J; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Roslagstullsbacken 21, Stockholm 114 17, Sweden.; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala 75185, Sweden., Gräslund T; Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Roslagstullsbacken 21, Stockholm 114 17, Sweden., Santos HA; Department of Biomaterials and Biomedical Technology, University Medical Center Groningen, University of Groningen, AV Groningen 9713, the Netherlands.; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, Helsinki FI-00014, Finland., Sarmento B; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen 208, Porto 4200-135, Portugal.; Instituto Universitário de Ciências da Saúde (IUCS-CESPU), Rua Central de Gandra 1317, Gandra 4585-116, Portugal.
Jazyk:	angličtina
Zdroj:	ACS nano [ACS Nano] 2024 Oct 15; Vol. 18 (41), pp. 28406-28424. Date of Electronic Publication: 2024 Oct 02.
DOI:	10.1021/acsnano.4c11172
Abstrakt:	The oral administration of the glucagon-like peptide-1 analogue, semaglutide, remains a hurdle due to its limited bioavailability. Herein, neonatal Fc receptor (FcRn)-targeted nanoparticles (NPs) were designed to enhance the oral delivery of semaglutide. The nanocarriers were covalently linked to the FcRn-binding peptide FcBP or the affibody molecule Z FcRn that specifically binds to the human FcRn (hFcRn) in a pH-dependent manner. These FcRn-targeted ligands were selected over the endogenous ligands of the receptor (albumin and IgG) due to their smaller size and simpler structure, which could facilitate the transport of functionalized NPs through the tissues. The capacity of FcRn-targeted semaglutide-NPs in controlling the blood glucose levels was evaluated in an hFcRn transgenic mice model, where type 2 diabetes mellitus (T2DM) was induced via intraperitoneal injection of nicotinamide followed by streptozotocin. The encapsulation of semaglutide into FcRn-targeted NPs was translated in an improved glucoregulatory effect in T2DM-induced mice when compared to the oral free semaglutide or nontargeted NP groups, after daily oral administrations for 7 days. Notably, a similar glucose-lowering response was observed between both FcRn-targeted NPs and the subcutaneous semaglutide groups. An increase in insulin pancreatic content and a recovery in β cell mass were visualized in the mice treated with FcRn-targeted semaglutide-NPs. The biodistribution of fluorescently labeled NPs through the gastrointestinal tract demonstrated that the nanosystems targeting the hFcRn are retained longer in the ileum and colorectum, where the expression of FcRn is more prevalent, than nontargeted NPs. Therefore, FcRn-targeted nanocarriers proved to be an effective platform for improving the pharmacological effect of semaglutide in a T2DM-induced mice model.
Databáze:	MEDLINE
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