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Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates

Cellular uptake and antisense activity of d-octaarginine conjugated peptide nucleic acids (PNAs) is shown to exhibit pronounced cooperativity in serum-containing medium, in particular by being enhanced by analogous mis-match PNA–cell-penetrating peptide (PNA–CPP) conjugates without inherent antisens...

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Autores principales: Ghavami, Mahdi, Shiraishi, Takehiko, Nielsen, Peter E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843268/
https://www.ncbi.nlm.nih.gov/pubmed/31581514
http://dx.doi.org/10.3390/biom9100554
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author Ghavami, Mahdi
Shiraishi, Takehiko
Nielsen, Peter E.
author_facet Ghavami, Mahdi
Shiraishi, Takehiko
Nielsen, Peter E.
author_sort Ghavami, Mahdi
collection PubMed
description Cellular uptake and antisense activity of d-octaarginine conjugated peptide nucleic acids (PNAs) is shown to exhibit pronounced cooperativity in serum-containing medium, in particular by being enhanced by analogous mis-match PNA–cell-penetrating peptide (PNA–CPP) conjugates without inherent antisense activity. This cooperativity does not show cell or PNA sequence dependency, suggesting that it is a common effect in cationic CPP conjugated PNA delivery. Interestingly, our results also indicate that Deca-r8-PNA and r8-PNA could assist each other and even other non-CPP PNAs as an uptake enhancer agent. However, the peptide itself (without being attached to the PNA) failed to enhance uptake and antisense activity. These results are compatible with an endosomal uptake mechanism in which the endocytosis event is induced by multiple CPP–PNA binding to the cell surface requiring a certain CPP density, possibly in terms of nanoparticle number and/or size, to be triggered. In particular the finding that the number of endosomal events is dependent on the total CPP–PNA concentration supports such a model. It is not possible from the present results to conclude whether endosomal escape is also cooperatively induced by CPP–PNA.
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spelling pubmed-68432682019-11-25 Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates Ghavami, Mahdi Shiraishi, Takehiko Nielsen, Peter E. Biomolecules Article Cellular uptake and antisense activity of d-octaarginine conjugated peptide nucleic acids (PNAs) is shown to exhibit pronounced cooperativity in serum-containing medium, in particular by being enhanced by analogous mis-match PNA–cell-penetrating peptide (PNA–CPP) conjugates without inherent antisense activity. This cooperativity does not show cell or PNA sequence dependency, suggesting that it is a common effect in cationic CPP conjugated PNA delivery. Interestingly, our results also indicate that Deca-r8-PNA and r8-PNA could assist each other and even other non-CPP PNAs as an uptake enhancer agent. However, the peptide itself (without being attached to the PNA) failed to enhance uptake and antisense activity. These results are compatible with an endosomal uptake mechanism in which the endocytosis event is induced by multiple CPP–PNA binding to the cell surface requiring a certain CPP density, possibly in terms of nanoparticle number and/or size, to be triggered. In particular the finding that the number of endosomal events is dependent on the total CPP–PNA concentration supports such a model. It is not possible from the present results to conclude whether endosomal escape is also cooperatively induced by CPP–PNA. MDPI 2019-10-01 /pmc/articles/PMC6843268/ /pubmed/31581514 http://dx.doi.org/10.3390/biom9100554 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ghavami, Mahdi
Shiraishi, Takehiko
Nielsen, Peter E.
Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates
title Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates
title_full Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates
title_fullStr Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates
title_full_unstemmed Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates
title_short Cooperative Cellular Uptake and Activity of Octaarginine Antisense Peptide Nucleic Acid (PNA) Conjugates
title_sort cooperative cellular uptake and activity of octaarginine antisense peptide nucleic acid (pna) conjugates
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843268/
https://www.ncbi.nlm.nih.gov/pubmed/31581514
http://dx.doi.org/10.3390/biom9100554
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