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A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy

The ability to specifically block or degrade cytosolic targets using therapeutic proteins would bring tremendous therapeutic opportunities in cancer therapy. Over the last few years, significant progress has been made with respect to tissue targeting, cytosolic delivery, and catalytic inactivation o...

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Autores principales: Torres, Camilo, Dumas, Simon, Palacio-Castañeda, Valentina, Descroix, Stéphanie, Brock, Roland, Verdurmen, Wouter P. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071550/
https://www.ncbi.nlm.nih.gov/pubmed/33921165
http://dx.doi.org/10.3390/pharmaceutics13040562
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author Torres, Camilo
Dumas, Simon
Palacio-Castañeda, Valentina
Descroix, Stéphanie
Brock, Roland
Verdurmen, Wouter P. R.
author_facet Torres, Camilo
Dumas, Simon
Palacio-Castañeda, Valentina
Descroix, Stéphanie
Brock, Roland
Verdurmen, Wouter P. R.
author_sort Torres, Camilo
collection PubMed
description The ability to specifically block or degrade cytosolic targets using therapeutic proteins would bring tremendous therapeutic opportunities in cancer therapy. Over the last few years, significant progress has been made with respect to tissue targeting, cytosolic delivery, and catalytic inactivation of targets, placing this aim within reach. Here, we developed a mathematical model specifically built for the evaluation of approaches towards cytosolic protein delivery, involving all steps from systemic administration to translocation into the cytosol and target engagement. Focusing on solid cancer tissues, we utilized the model to investigate the effects of microvascular permeability, receptor affinity, the cellular density of targeted receptors, as well as the mode of activity (blocking/degradation) on therapeutic potential. Our analyses provide guidance for the rational optimization of protein design for enhanced activity and highlight the importance of tuning the receptor affinity as a function of receptor density as well as the receptor internalization rate. Furthermore, we provide quantitative insights into how enzymatic cargoes can enhance the distribution, extent, and duration of therapeutic activity, already at very low catalytic rates. Our results illustrate that with current protein engineering approaches, the goal of delivery of cytosolic delivery of proteins for therapeutic effects is well within reach.
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spelling pubmed-80715502021-04-26 A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy Torres, Camilo Dumas, Simon Palacio-Castañeda, Valentina Descroix, Stéphanie Brock, Roland Verdurmen, Wouter P. R. Pharmaceutics Article The ability to specifically block or degrade cytosolic targets using therapeutic proteins would bring tremendous therapeutic opportunities in cancer therapy. Over the last few years, significant progress has been made with respect to tissue targeting, cytosolic delivery, and catalytic inactivation of targets, placing this aim within reach. Here, we developed a mathematical model specifically built for the evaluation of approaches towards cytosolic protein delivery, involving all steps from systemic administration to translocation into the cytosol and target engagement. Focusing on solid cancer tissues, we utilized the model to investigate the effects of microvascular permeability, receptor affinity, the cellular density of targeted receptors, as well as the mode of activity (blocking/degradation) on therapeutic potential. Our analyses provide guidance for the rational optimization of protein design for enhanced activity and highlight the importance of tuning the receptor affinity as a function of receptor density as well as the receptor internalization rate. Furthermore, we provide quantitative insights into how enzymatic cargoes can enhance the distribution, extent, and duration of therapeutic activity, already at very low catalytic rates. Our results illustrate that with current protein engineering approaches, the goal of delivery of cytosolic delivery of proteins for therapeutic effects is well within reach. MDPI 2021-04-15 /pmc/articles/PMC8071550/ /pubmed/33921165 http://dx.doi.org/10.3390/pharmaceutics13040562 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
Torres, Camilo
Dumas, Simon
Palacio-Castañeda, Valentina
Descroix, Stéphanie
Brock, Roland
Verdurmen, Wouter P. R.
A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy
title A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy
title_full A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy
title_fullStr A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy
title_full_unstemmed A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy
title_short A Computational Investigation of In Vivo Cytosolic Protein Delivery for Cancer Therapy
title_sort computational investigation of in vivo cytosolic protein delivery for cancer therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071550/
https://www.ncbi.nlm.nih.gov/pubmed/33921165
http://dx.doi.org/10.3390/pharmaceutics13040562
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