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Statin-boosted cellular uptake and endosomal escape of penetratin due to reduced membrane dipole potential
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  • Gyula Batta,
  • Levente Karpati,
  • Gabriela Fulaneto,
  • Szabolcs Tarapcsak,
  • Tamas Kovacs,
  • Florina Zakany,
  • Istvan Mandity,
  • Peter Nagy
Gyula Batta
University of Debrecen
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Levente Karpati
Semmelweis Egyetem
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Gabriela Fulaneto
University of Debrecen
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Szabolcs Tarapcsak
University of Debrecen
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Tamas Kovacs
University of Debrecen
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Florina Zakany
University of Debrecen
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Istvan Mandity
Semmelweis Egyetem
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Peter Nagy
University of Debrecen
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Abstract

Since cell penetrating peptides are promising tools for delivery of cargo into cells, factors limiting or facilitating their cellular uptake are intensely studied. Using labeling with pH-insensitive and pH-sensitive dyes we report that escape of penetratin from acidic endo-lysosomal compartments is retarded compared to its total cellular uptake. The membrane dipole potential, known to alter transmembrane transport of charged molecules, is shown to be negatively correlated with the concentration of penetratin in the cytoplasmic compartment. Treatment of cells with therapeutically relevant concentrations of atorvastatin, an inhibitor of HMG-CoA reductase and cholesterol synthesis, significantly increased endosomal escape of penetratin in two different cell types. This effect of atorvastatin correlated with its ability to decrease the membrane dipole potential. These results highlight the importance of the dipole potential in regulating cellular uptake of cell penetrating peptides and suggest a clinically relevant way of boosting this process.

Peer review status:Published

22 Sep 2020Submitted to British Journal of Pharmacology
23 Sep 2020Submission Checks Completed
23 Sep 2020Assigned to Editor
29 Sep 2020Reviewer(s) Assigned
01 Nov 2020Review(s) Completed, Editorial Evaluation Pending
14 Nov 2020Editorial Decision: Revise Minor
21 Mar 20211st Revision Received
22 Mar 2021Submission Checks Completed
22 Mar 2021Assigned to Editor
27 Mar 2021Reviewer(s) Assigned
05 Apr 2021Review(s) Completed, Editorial Evaluation Pending
18 Apr 2021Editorial Decision: Revise Minor
19 Apr 20212nd Revision Received
20 Apr 2021Submission Checks Completed
20 Apr 2021Assigned to Editor
24 Apr 2021Editorial Decision: Accept
28 Apr 2021Published in British Journal of Pharmacology. 10.1111/bph.15509