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Article Dans Une Revue (Article De Synthèse) ACS Nano Année : 2022

Barriers to the intestinal absorption of four insulin-loaded arginine-rich nanoparticles in human and rat

1 Departmentof Pharmacy,UppsalaUniversity,SE-75143 Uppsala,Swede
2 Departmentof Pharmacy,UppsalaUniversity,SE-75143 Uppsala,Sweden
3 Departmentof Pharmacyand PharmaceuticalTechnology,CIMUS,Universidadede SantiagodeCompostela,Santiagode CompostelaES 15782,Spain;
4 Departmentof PharmacyandPharmaceuticalTechnology,CIMUS,UniversidadedeSantiagode Compostela,Santiagode CompostelaES 15782,Spain;Universitécatholiquede Louvain,UCLouvain,LouvainDrugResearchInstitute,AdvancedDrugDeliveryand Biomaterials,BE 1200Brussels,Belgium;
5 UCDSchoolof VeterinaryMedicine,UniversityCollegeDublin,BelfieldD04V1W8,Ireland
6 Departmentof Surgeryin Norrköping,LinköpingUniversity,SE-58183 Norrköping,Sweden;Departmentof Biomedicaland ClinicalSciences,LinköpingUniversity,SE-58183 Linköping,Sweden
7 Universitécatholiquede Louvain,UCLouvain,LouvainDrugResearchInstitute,AdvancedDrugDeliveryand Biomaterials,BE 1200Brussels,Belgium
8 SPI - Service de Pharmacologie et Immunoanalyse
9 LENIT - Laboratoire d'Etude de l'Unité Neurovasculaire & Innovation Thérapeutique
10 MTS - Médicaments et Technologies pour la Santé
11 USC - Universidade de Santiago de Compostela [Spain]
12 Department of MedicalSciences,UppsalaUniversity,SE-75185 Uppsala,Sweden;
13 Department of MedicalSciences,UppsalaUniversity,SE-75185 Uppsala,Sweden
14 Departmentof Biomedicaland ClinicalSciences,LinköpingUniversity,SE-58183 Linköping,Sweden
15 Departmentof SurgicalSciences−UpperAbdominalSurgery,UppsalaUniversity,SE-75185 Uppsala,Sweden
16 Department of SurgicalSciences−UpperAbdominalSurgery,UppsalaUniversity,SE-75185 Uppsala,Sweden;
17 LDRI - Louvain Drug Research Institute [Bruxelles, Belgique]
18 DCU - Dublin City University [Dublin]
19 CIDAUT Foundation
David J Brayden
Maria Jose Alonso

Résumé

Peptide drugs and biologics provide opportunities for treatments of many diseases. However, due to their poor stability and permeability in the gastrointestinal tract, the oral bioavailability of peptide drugs is negligible. Nanoparticle formulations have been proposed to circumvent these hurdles, but systemic exposure of orally administered peptide drugs has remained elusive. In this study, we investigated the absorption mechanisms of four insulin-loaded arginine-rich nanoparticles displaying differing composition and surface characteristics, developed within the pan-European consortium TRANS-INT. The transport mechanisms and major barriers to nanoparticle permeability were investigated in freshly isolated human jejunal tissue. Cytokine release profiles and standard toxicity markers indicated that the nanoparticles were nontoxic. Three out of four nanoparticles displayed pronounced binding to the mucus layer and did not reach the epithelium. One nanoparticle composed of a mucus inert shell and cell-penetrating octarginine (ENCP), showed significant uptake by the intestinal epithelium corresponding to 28 ± 9% of the administered nanoparticle dose, as determined by super-resolution microscopy. Only a small fraction of nanoparticles taken up by epithelia went on to be transcytosed via a dynamin-dependent process. In situ studies in intact rat jejunal loops confirmed the results from human tissue regarding mucus binding, epithelial uptake, and negligible insulin bioavailability. In conclusion, while none of the four arginine-rich nanoparticles supported systemic insulin delivery, ENCP displayed a consistently high uptake along the intestinal villi. It is proposed that ENCP should be further investigated for local delivery of therapeutics to the intestinal mucosa.
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Dates et versions

hal-04476193 , version 1 (24-02-2024)

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Citer

Patrik Lundquist, Georgiy Khodus, Zhigao Niu, Lungile Nomcebo Thwala, Fiona Mccartney, et al.. Barriers to the intestinal absorption of four insulin-loaded arginine-rich nanoparticles in human and rat. ACS Nano, 2022, 16 (9), pp.14210-14229. ⟨10.1021/acsnano.2c04330⟩. ⟨hal-04476193⟩
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