title: Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers.
abstract: The aim of this work was to rationally design and characterize nanocapsules (NCs) composed of an oily core and a polyarginine (PARG) shell, intended for oral peptide delivery. The cationic polyaminoacid, PARG, and the oily core components were selected based on their penetration enhancing properties. Insulin was adopted as a model peptide to assess the performance of the NCs. After screening numerous formulation variables, including different oils and surfactants, we defined a composition consisting of oleic acid, sodium deoxycholate (SDC) and Span 80. This selected NCs composition, produced by the solvent displacement technique, exhibited the following key features: (i) an average size of 180nm and a low polydispersity (0.1), (ii) a high insulin association efficacy (80-90% AE), (iii) a good colloidal stability upon incubation in simulated intestinal fluids (SIF, FaSSIF-V2, FeSSIF-V2), and (iv) the capacity to control the release of the associated insulin for >4h. Furthermore, using the Caco-2 model cell line, PARG nanocapsules were able to interact with the enterocytes, and reversibly modify the TEER of the monolayer. Both cell adhesion and membrane permeabilization could account for the pronounced transport of the NCs-associated insulin (3.54%). This improved interaction was also visualized by confocal fluorescent microscopy following oral administration of PARG nanocapsulesto mice. Finally, in vivo efficacy studies performed in normoglycemic rats showed a significant decrease in their plasma glucose levels after treatment. In conclusion, here we disclose key formulation elements for making possible the oral administration of peptides.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, CIMUS Research Institute, IDIS research Institute, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Zhigao
authors.initials: Z
authors.lastname: Niu
authors.affiliation: ECSIN-European Center for the Sustainable Impact of Nanotechnology, ECAMRICERT SRL, I-45100 Rovigo, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Tedesco
authors.affiliation: ECSIN-European Center for the Sustainable Impact of Nanotechnology, ECAMRICERT SRL, I-45100 Rovigo, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Benetti
authors.affiliation: Service de Pharmacologie et d'Immunoanalyse, IBITECS, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France.
authors.forename: Aloïse
authors.initials: A
authors.lastname: Mabondzo
authors.affiliation: Veneto Institute of Oncology, IOV-IRCCS, 35128 Padova, Italy.
authors.forename: Isabella Monia
authors.initials: IM
authors.lastname: Montagner
authors.affiliation: Veneto Institute of Oncology, IOV-IRCCS, 35128 Padova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marigo
authors.affiliation: Biomedical Research Group, Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez-Touceda
authors.affiliation: Biomedical Research Group, Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Sulay
authors.initials: S
authors.lastname: Tovar
authors.affiliation: Biomedical Research Group, Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, CIMUS Research Institute, IDIS research Institute, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; Cellular Neurobiology and Molecular Chemistry of the Central Nervous System Group, Universidad de Castilla-La Mancha, Spain.
authors.forename: Manuel J
authors.initials: MJ
authors.lastname: Santander-Ortega
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, CIMUS Research Institute, IDIS research Institute, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address: mariajalonso@usc.es.
authors.forename: María J
authors.initials: MJ
authors.lastname: Alonso
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D018938:Caco-2 Cells; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry; D015195:Drug Design; D065546:Drug Liberation; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007419:Intestinal Secretions / Q000737:chemistry; D008297:Male; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D007328:Insulin; D053769:Nanocapsules; D010455:Peptides; C015462:polyarginine
keywords: Insulin; Nanocapsule; Oral peptide delivery; Permeation enhancer; Polyarginine