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Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy

Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuab...

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Autores principales: Faria, Rúben, Paul, Milan, Biswas, Swati, Vivès, Eric, Boisguérin, Prisca, Sousa, Ângela, Costa, Diana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026848/
https://www.ncbi.nlm.nih.gov/pubmed/35456591
http://dx.doi.org/10.3390/pharmaceutics14040757
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author Faria, Rúben
Paul, Milan
Biswas, Swati
Vivès, Eric
Boisguérin, Prisca
Sousa, Ângela
Costa, Diana
author_facet Faria, Rúben
Paul, Milan
Biswas, Swati
Vivès, Eric
Boisguérin, Prisca
Sousa, Ângela
Costa, Diana
author_sort Faria, Rúben
collection PubMed
description Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and promising therapeutic tool. To accomplish this goal, the design/development of a mitochondrial-specific gene delivery system is imperative. In this work, we explored the ability of novel polymer- and peptide-based systems for mitochondrial targeting, gene delivery, and protein expression, performing a comparison between them to reveal the most adequate system for mitochondrial gene therapy. Therefore, we synthesized a novel mitochondria-targeting polymer (polyethylenimine–dequalinium) to load and complex a mitochondrial-gene-based plasmid. The polymeric complexes exhibited physicochemical properties and cytotoxic profiles dependent on the nitrogen-to-phosphate-group ratio (N/P). A fluorescence confocal microscopy study revealed the mitochondrial targeting specificity of polymeric complexes. Moreover, transfection mediated by polymer and peptide delivery systems led to gene expression in mitochondria. Additionally, the mitochondrial protein was produced. A comparative study between polymeric and peptide/plasmid DNA complexes showed the great capacity of peptides to complex pDNA at lower N/P ratios, forming smaller particles bearing a positive charge, with repercussions on their capacity for cellular transfection, mitochondria targeting and, ultimately, gene delivery and protein expression. This report is a significant contribution to the implementation of mitochondrial gene therapy, instigating further research on the development of peptide-based delivery systems towards clinical translation.
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spelling pubmed-90268482022-04-23 Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy Faria, Rúben Paul, Milan Biswas, Swati Vivès, Eric Boisguérin, Prisca Sousa, Ângela Costa, Diana Pharmaceutics Article Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and promising therapeutic tool. To accomplish this goal, the design/development of a mitochondrial-specific gene delivery system is imperative. In this work, we explored the ability of novel polymer- and peptide-based systems for mitochondrial targeting, gene delivery, and protein expression, performing a comparison between them to reveal the most adequate system for mitochondrial gene therapy. Therefore, we synthesized a novel mitochondria-targeting polymer (polyethylenimine–dequalinium) to load and complex a mitochondrial-gene-based plasmid. The polymeric complexes exhibited physicochemical properties and cytotoxic profiles dependent on the nitrogen-to-phosphate-group ratio (N/P). A fluorescence confocal microscopy study revealed the mitochondrial targeting specificity of polymeric complexes. Moreover, transfection mediated by polymer and peptide delivery systems led to gene expression in mitochondria. Additionally, the mitochondrial protein was produced. A comparative study between polymeric and peptide/plasmid DNA complexes showed the great capacity of peptides to complex pDNA at lower N/P ratios, forming smaller particles bearing a positive charge, with repercussions on their capacity for cellular transfection, mitochondria targeting and, ultimately, gene delivery and protein expression. This report is a significant contribution to the implementation of mitochondrial gene therapy, instigating further research on the development of peptide-based delivery systems towards clinical translation. MDPI 2022-03-31 /pmc/articles/PMC9026848/ /pubmed/35456591 http://dx.doi.org/10.3390/pharmaceutics14040757 Text en © 2022 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
Faria, Rúben
Paul, Milan
Biswas, Swati
Vivès, Eric
Boisguérin, Prisca
Sousa, Ângela
Costa, Diana
Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy
title Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy
title_full Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy
title_fullStr Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy
title_full_unstemmed Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy
title_short Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy
title_sort peptides vs. polymers: searching for the most efficient delivery system for mitochondrial gene therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026848/
https://www.ncbi.nlm.nih.gov/pubmed/35456591
http://dx.doi.org/10.3390/pharmaceutics14040757
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