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Stereoisomer-dependent membrane association and capacity for insulin delivery facilitated by Penetratin

Birch, Ditlev, Sayers, Edward J. ORCID:, Christensen, Malene V., Jones, Arwyn T. ORCID:, Franzyk, Henrik and Nielsen, Hanne M. 2023. Stereoisomer-dependent membrane association and capacity for insulin delivery facilitated by Penetratin. Pharmaceutics 15 (6) , 1672. 10.3390/pharmaceutics15061672

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Cell-penetrating peptides (CPPs), such as penetratin, are often investigated as drug delivery vectors and incorporating d-amino acids, rather than the natural l-forms, to enhance proteolytic stability could improve their delivery efficiency. The present study aimed to compare membrane association, cellular uptake, and delivery capacity for all-l and all-d enantiomers of penetratin (PEN) by using different cell models and cargos. The enantiomers displayed widely different distribution patterns in the examined cell models, and in Caco-2 cells, quenchable membrane binding was evident for d-PEN in addition to vesicular intracellular localization for both enantiomers. The uptake of insulin in Caco-2 cells was equally mediated by the two enantiomers, and while l-PEN did not increase the transepithelial permeation of any of the investigated cargo peptides, d-PEN increased the transepithelial delivery of vancomycin five-fold and approximately four-fold for insulin at an extracellular apical pH of 6.5. Overall, while d-PEN was associated with the plasma membrane to a larger extent and was superior in mediating the transepithelial delivery of hydrophilic peptide cargoes compared to l-PEN across Caco-2 epithelium, no enhanced delivery of the hydrophobic cyclosporin was observed, and intracellular insulin uptake was induced to a similar degree by the two enantiomers.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Pharmacy
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: MDPI
ISSN: 1999-4923
Date of First Compliant Deposit: 10 July 2023
Date of Acceptance: 26 May 2023
Last Modified: 06 Jan 2024 04:34

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