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Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo

Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therape...

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Autores principales: Bazaz, Safa, Lehto, Tõnis, Tops, Rahel, Gissberg, Olof, Gupta, Dhanu, Bestas, Burcu, Bost, Jeremy, Wiklander, Oscar P. B., Sork, Helena, Zaghloul, Eman M., Mamand, Doste R., Hällbrink, Mattias, Sillard, Rannar, Saher, Osama, Ezzat, Kariem, Smith, C. I. Edvard, Andaloussi, Samir EL, Lehto, Taavi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392223/
https://www.ncbi.nlm.nih.gov/pubmed/34440250
http://dx.doi.org/10.3390/biomedicines9081046
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author Bazaz, Safa
Lehto, Tõnis
Tops, Rahel
Gissberg, Olof
Gupta, Dhanu
Bestas, Burcu
Bost, Jeremy
Wiklander, Oscar P. B.
Sork, Helena
Zaghloul, Eman M.
Mamand, Doste R.
Hällbrink, Mattias
Sillard, Rannar
Saher, Osama
Ezzat, Kariem
Smith, C. I. Edvard
Andaloussi, Samir EL
Lehto, Taavi
author_facet Bazaz, Safa
Lehto, Tõnis
Tops, Rahel
Gissberg, Olof
Gupta, Dhanu
Bestas, Burcu
Bost, Jeremy
Wiklander, Oscar P. B.
Sork, Helena
Zaghloul, Eman M.
Mamand, Doste R.
Hällbrink, Mattias
Sillard, Rannar
Saher, Osama
Ezzat, Kariem
Smith, C. I. Edvard
Andaloussi, Samir EL
Lehto, Taavi
author_sort Bazaz, Safa
collection PubMed
description Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) are a class of drug delivery systems (DDSs) that have recently gained considerable attention for improving the uptake of various oligonucleotide (ON)-based compounds, including SSOs. One strategy that has been successfully applied to develop effective CPP vectors is the introduction of various lipid modifications into the peptide. Here, we repurpose hydrocarbon-modified amino acids used in peptide stapling for the orthogonal introduction of hydrophobic modifications into the CPP structure during peptide synthesis. Our data show that α,α-disubstituted alkenyl-alanines can be successfully utilized to introduce hydrophobic modifications into CPPs to improve their ability to formulate SSOs into nanoparticles (NPs), and to mediate high delivery efficacy and tolerability both in vitro and in vivo. Conclusively, our results offer a new flexible approach for the sequence-specific introduction of hydrophobicity into the structure of CPPs and for improving their delivery properties.
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spelling pubmed-83922232021-08-28 Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo Bazaz, Safa Lehto, Tõnis Tops, Rahel Gissberg, Olof Gupta, Dhanu Bestas, Burcu Bost, Jeremy Wiklander, Oscar P. B. Sork, Helena Zaghloul, Eman M. Mamand, Doste R. Hällbrink, Mattias Sillard, Rannar Saher, Osama Ezzat, Kariem Smith, C. I. Edvard Andaloussi, Samir EL Lehto, Taavi Biomedicines Article Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) are a class of drug delivery systems (DDSs) that have recently gained considerable attention for improving the uptake of various oligonucleotide (ON)-based compounds, including SSOs. One strategy that has been successfully applied to develop effective CPP vectors is the introduction of various lipid modifications into the peptide. Here, we repurpose hydrocarbon-modified amino acids used in peptide stapling for the orthogonal introduction of hydrophobic modifications into the CPP structure during peptide synthesis. Our data show that α,α-disubstituted alkenyl-alanines can be successfully utilized to introduce hydrophobic modifications into CPPs to improve their ability to formulate SSOs into nanoparticles (NPs), and to mediate high delivery efficacy and tolerability both in vitro and in vivo. Conclusively, our results offer a new flexible approach for the sequence-specific introduction of hydrophobicity into the structure of CPPs and for improving their delivery properties. MDPI 2021-08-19 /pmc/articles/PMC8392223/ /pubmed/34440250 http://dx.doi.org/10.3390/biomedicines9081046 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bazaz, Safa
Lehto, Tõnis
Tops, Rahel
Gissberg, Olof
Gupta, Dhanu
Bestas, Burcu
Bost, Jeremy
Wiklander, Oscar P. B.
Sork, Helena
Zaghloul, Eman M.
Mamand, Doste R.
Hällbrink, Mattias
Sillard, Rannar
Saher, Osama
Ezzat, Kariem
Smith, C. I. Edvard
Andaloussi, Samir EL
Lehto, Taavi
Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo
title Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo
title_full Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo
title_fullStr Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo
title_full_unstemmed Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo
title_short Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo
title_sort novel orthogonally hydrocarbon-modified cell-penetrating peptide nanoparticles mediate efficient delivery of splice-switching antisense oligonucleotides in vitro and in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392223/
https://www.ncbi.nlm.nih.gov/pubmed/34440250
http://dx.doi.org/10.3390/biomedicines9081046
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