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

JOURNAL OF CONTROLLED RELEASE

卷:263

Article; Proceedings Paper

Niu, Zhigao¹  Tedesco, Erik²  Benetti, Federico²  Mabondzo, Aloise³  Montagner, IsabellaMonia⁴  Marigo, Ilaria⁴  Gonzalez-Touceda, David⁵  Tovar, Sulay⁵  Dieguez, Carlos⁵  Santander-Ortega, Manuel J.^1,6  Alonso, Maria J.¹ 

[1] Univ Santiago de Compostela, CIMUS Res Inst, IDIS Res Inst, Dept Pharm & Pharmaceut Technol, Santiago De Compostela 15782, Spain

[2] ECAMRICERT SRL, ECSIN, I-45100 Rovigo, Italy

[3] Univ Paris Saclay, Serv Pharmacol & Immunoanal, IBITECS, CEA, F-91191 Gif Sur Yvette, France

[4] IOV IRCCS, Veneto Inst Oncol, I-35128 Padua, Italy

[5] Univ Santiago de Compostela, Biomed Res Grp, Ctr Res Mol Med & Chron Dis, Santiago De Compostela 15782, Spain

[6] Univ Castilla La Mancha, Cent Nervous Syst Grp, Cellular Neurobiol & Mol Chem, Ciudad Real, Spain

关键词: Polyarginine;    Nanocapsule;    Insulin;    Permeation enhancer;    Oral peptide delivery;   

DOI  :  10.1016/j.jconrel.2017.02.024

来源: Elsevier

【 摘 要 】

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 amodel 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. (C) 2017 The Authors. Published by Elsevier B.V.

【 授权许可】

Free