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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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. |
format | Online Article Text |
id | pubmed-8071550 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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