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J Control Release. 2018 Apr 28;276:125-139. doi: 10.1016/j.jconrel.2018.03.004. Epub 2018 Mar 6.

PEG-PGA enveloped octaarginine-peptide nanocomplexes: An oral peptide delivery strategy.

Author information

1
Center for Research in Molecular Medicine and Chronic Diseases, IDIS research Institute, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
2
Service de Pharmacologie et d'Immunoanalyse, IBITECS, CEA, Université Paris-Saclay, F-91191 Gif-sur-Yvette, France.
3
Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Université Catholique de Louvain, B-1200 Brussels, Belgium.
4
Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute for Science and Technology (BIST), 08028 Barcelona, Spain.
5
Biomedical Research Group, Center for Research in Molecular Medicine and Chronic Diseases, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
6
Cellular Neuroanatomy, Molecular Chemistry of Central Nervous System Group, Faculty of Pharmacy, University of Castilla-La Mancha, 02071 Albacete, Spain; Regional Centre of Biomedical Research (CRIB), University of Castilla-La Mancha, Albacete, Spain.
7
Radiopharmacy Unit, Department of Nuclear Medicine, Clínica Universidad de Navarra, University Clinic of Navarra, 31008 Pamplona, Spain.
8
Center for Research in Molecular Medicine and Chronic Diseases, IDIS research Institute, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address: mariaj.alonso@usc.es.

Abstract

The objective of this work was the development of a new drug nanocarrier intended to overcome the barriers associated to the oral modality of administration and to assess its value for the systemic or local delivery of peptides. The nanocarrier was rationally designed taking into account the nature of the intestinal barriers and was loaded with insulin, which was selected as a model peptide. The nanocarrier consisted of a complex between insulin and a hydrophobically-modified cell penetrating peptide (CPP), enveloped by a protecting polymer. The selected CPP was octaarginine (r8), chemically conjugated with cholesterol (Chol) or lauric acid (C12), whereas the protecting polymer was poly (glutamic acid)-poly (ethylene glycol) (PGA-PEG). This enveloping material was intended to preserve the stability of the nanocomplex in the intestinal medium and facilitate its diffusion across the intestinal mucus. The enveloped nanocomplexes (ENCPs) exhibited a number of key features, namely (i) a unimodal size distribution with a mean size of 200 nm and a neutral zeta potential, (ii) the capacity to associate insulin (~100% association efficiency) and protect it from degradation in simulated intestinal fluids, (iii) the ability to diffuse through intestinal mucus and, most importantly, (iv) the capacity to interact with the Caco-2 model epithelium, resulting in a massive insulin cell uptake (47.59 ± 5.79%). This enhanced accumulation of insulin at the epithelial level was not translated into an enhanced insulin transport. In fact, only 2% of insulin was transported across the monolayer, and this was correlated with a moderate response of insulin following oral administration to healthy rats. Despite of this, the accumulation of the insulin-loaded nanocarriers in the intestinal mucosa could be verified in vivo upon their labeling with 99mTc. Overall, these data underline the capacity of the nanocarriers to overcome substantial barriers associated to the oral modality of administration and to facilitate the accumulation of the associated peptide at the intestinal level.

KEYWORDS:

Cell penetrating peptide; Nanocomplex; Octaarginine; Oral peptide/protein delivery; PEGylation

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