title: Dual chitosan/albumin-coated alginate/dextran sulfate nanoparticles for enhanced oral delivery of insulin.
abstract: The potential of nanoparticles (NPs) to overcome the barriers for oral delivery of protein drugs have led to the development of platforms capable of improving their bioavailability. However, despite the progresses in drug delivery technologies, the success of oral delivery of insulin remains elusive and the disclosure of insulin mechanisms of absorption remains to be clarified. To overcome multiple barriers faced by oral insulin and to enhance the insulin permeability across the intestinal epithelium, here insulin-loaded alginate/dextran sulfate (ADS)-NPs were formulated and dual-coated with chitosan (CS) and albumin (ALB). The nanosystem was characterized by its pH-sensitivity and mucoadhesivity, which enabled to prevent 70% of in vitro insulin release in simulated gastric conditions and allowed a sustained insulin release following the passage to simulated intestinal conditions. The pH and time-dependent morphology of the NPs was correlated to the release and permeation profile of insulin. Dual CS/ALB coating of the ADS-NPs demonstrated augmented intestinal interactions with the intestinal cells in comparison to the uncoated-NPs, resulting in a higher permeability of insulin across Caco-2/HT29-MTX/Raji B cell monolayers. The permeability of the insulin-loaded ALB-NPs was reduced after the temperature was decreased and after co-incubation with chlorpromazine, suggesting an active insulin transport by clathrin-mediated endocytosis. Moreover, the permeability inhibition with the pre-treatment with sodium chlorate suggested that the interaction between glycocalix and the NPs was critical for insulin permeation. Overall, the developed nanosystem has clinical potential for the oral delivery of insulin and therapy of type 1 diabetes mellitus.
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CNrC-Center for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal.
authors.forename: Marlene
authors.initials: M
authors.lastname: Lopes
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Neha
authors.initials: N
authors.lastname: Shrestha
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Correia
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Shahbazi
authors.affiliation: CESPU, Instituto de Investigacão e Formacão Avançada em Ciências e Tecnologias da Saúde, 4585-116 Gandra, Portugal; INEB-Instituto de Engenharia Biomédica, University of Porto, 4150-180 Porto, Portugal; I3S-Instituto de Investigacão e Inovacão em Saúde, University of Porto, 4150-180 Porto, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Sarmento
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Jouni
authors.initials: J
authors.lastname: Hirvonen
authors.affiliation: Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; CNrC-Center for Neuroscience and Cell Biology, 3004-504 Coimbra, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Veiga
authors.affiliation: IBILI-Instituto de Imagem Biomédica e Ciências da Vida, 3000-548 Coimbra, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seiça
authors.affiliation: Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal; I3S-Instituto de Investigacão e Inovacão em Saúde, University of Porto, 4150-180 Porto, Portugal; IBMC-Instituto de Biologia Molecular e Celular, 4150-180 Porto, Portugal. Electronic address: aribeiro@ff.uc.pt.
authors.forename: António
authors.initials: A
authors.lastname: Ribeiro
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland. Electronic address: helder.santos@helsinki.fi.
authors.forename: Hélder A
authors.initials: HA
authors.lastname: Santos
mesh_terms: D000284:Administration, Oral; D000418:Albumins / Q000008:administration & dosage* / Q000737:chemistry; D018938:Caco-2 Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000008:administration & dosage*; D016264:Dextran Sulfate / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D019073:HT29 Cells; D006801:Humans; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000418:Albumins; D007328:Insulin; D048271:Chitosan; D016264:Dextran Sulfate
keywords: Diabetes; Insulin; Nanoparticles; Oral delivery; Triple co-culture; Uptake mechanisms