Journal
AAPS JOURNAL
Volume 17, Issue 5, Pages 1200-1209Publisher
SPRINGER
DOI: 10.1208/s12248-015-9747-3
Keywords
Caco-2 cell culture model; carrier peptide; insulin; penetratin; transepithelial permeation
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Funding
- Drug Research Academy, University of Copenhagen
- Danish Agency for Science, Technology and Innovation
- Novo Nordisk A/S
- FP7 Marie-Curie Actions Intra European Fellowship (IEF) for Career Development at the University of Copenhagen, Denmark [299385]
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Penetratin is a widely used carrier peptide showing promising potential for mucosal delivery of therapeutic proteins. In the present study, the importance of specific penetratin residues and pH was investigated with respect to complexation with insulin and subsequent transepithelial insulin permeation. Besides penetratin, three analogues were studied. The carrier peptide-insulin complexes were characterized in terms of size and morphology at pH 5, 6.5, and 7.4 by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. At pH 7.4 mainly very large complexes were present, while much smaller complexes dominated at pH 5. Presence of arginine residues in the carrier peptide proved to be a prerequisite for complexation with insulin as well as for enhanced transepithelial insulin permeation in vitro. Rearrangement of tryptophan residues resulted in significantly increased insulin permeation as compared to that of the parent penetratin. In general, pre-complexation with penetratin and its analogues at pH 5 gave rise to increased insulin permeation as compared to that observed at pH 7.4; this finding was further supported by a preliminary in vivo study using the parent penetratin.
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