Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers

Zhigao Niu, Erik Tedesco, Federico Benetti, Aloïse Mabondzo, Isabella Monia Montagner, Ilaria Marigo, David Gonzalez-Touceda, Sulay Tovar, Carlos Diéguez, Manuel J. Santander-Ortega, María J. Alonso

Research output: Contribution to journalArticle

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 180 nm 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 > 4 h. 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.

Original languageEnglish
Pages (from-to)4-17
Number of pages14
JournalJournal of Controlled Release
Volume263
DOIs
Publication statusPublished - Oct 10 2017

Keywords

  • Insulin
  • Nanocapsule
  • Oral peptide delivery
  • Permeation enhancer
  • Polyarginine

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Niu, Z., Tedesco, E., Benetti, F., Mabondzo, A., Montagner, I. M., Marigo, I., Gonzalez-Touceda, D., Tovar, S., Diéguez, C., Santander-Ortega, M. J., & Alonso, M. J. (2017). Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers. Journal of Controlled Release, 263, 4-17. https://doi.org/10.1016/j.jconrel.2017.02.024