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In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability
The delivery of blood-borne therapeutic agents to solid tumours depends on a broad range of biophysical factors. We present a novel multiscale, multiphysics, in-silico modelling framework that encompasses dynamic tumour growth, angiogenesis and drug delivery, and use this model to simulate the intra...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193741/ https://www.ncbi.nlm.nih.gov/pubmed/30296260 http://dx.doi.org/10.1371/journal.pcbi.1006460 |
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author | Vavourakis, Vasileios Stylianopoulos, Triantafyllos Wijeratne, Peter A. |
author_facet | Vavourakis, Vasileios Stylianopoulos, Triantafyllos Wijeratne, Peter A. |
author_sort | Vavourakis, Vasileios |
collection | PubMed |
description | The delivery of blood-borne therapeutic agents to solid tumours depends on a broad range of biophysical factors. We present a novel multiscale, multiphysics, in-silico modelling framework that encompasses dynamic tumour growth, angiogenesis and drug delivery, and use this model to simulate the intravenous delivery of cytotoxic drugs. The model accounts for chemo-, hapto- and mechanotactic vessel sprouting, extracellular matrix remodelling, mechano-sensitive vascular remodelling and collapse, intra- and extravascular drug transport, and tumour regression as an effect of a cytotoxic cancer drug. The modelling framework is flexible, allowing the drug properties to be specified, which provides realistic predictions of in-vivo vascular development and structure at different tumour stages. The model also enables the effects of neoadjuvant vascular normalisation to be implicitly tested by decreasing vessel wall pore size. We use the model to test the interplay between time of treatment, drug affinity rate and the size of the vessels’ endothelium pores on the delivery and subsequent tumour regression and vessel remodelling. Model predictions confirm that small-molecule drug delivery is dominated by diffusive transport and further predict that the time of treatment is important for low affinity but not high affinity cytotoxic drugs, the size of the vessel wall pores plays an important role in the effect of low affinity but not high affinity drugs, that high affinity cytotoxic drugs remodel the tumour vasculature providing a large window for the normalisation of the vascular architecture, and that the combination of large pores and high affinity enhances cytotoxic drug delivery efficiency. These results have implications for treatment planning and methods to enhance drug delivery, and highlight the importance of in-silico modelling in investigating the optimisation of cancer therapy on a personalised setting. |
format | Online Article Text |
id | pubmed-6193741 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-61937412018-11-05 In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability Vavourakis, Vasileios Stylianopoulos, Triantafyllos Wijeratne, Peter A. PLoS Comput Biol Research Article The delivery of blood-borne therapeutic agents to solid tumours depends on a broad range of biophysical factors. We present a novel multiscale, multiphysics, in-silico modelling framework that encompasses dynamic tumour growth, angiogenesis and drug delivery, and use this model to simulate the intravenous delivery of cytotoxic drugs. The model accounts for chemo-, hapto- and mechanotactic vessel sprouting, extracellular matrix remodelling, mechano-sensitive vascular remodelling and collapse, intra- and extravascular drug transport, and tumour regression as an effect of a cytotoxic cancer drug. The modelling framework is flexible, allowing the drug properties to be specified, which provides realistic predictions of in-vivo vascular development and structure at different tumour stages. The model also enables the effects of neoadjuvant vascular normalisation to be implicitly tested by decreasing vessel wall pore size. We use the model to test the interplay between time of treatment, drug affinity rate and the size of the vessels’ endothelium pores on the delivery and subsequent tumour regression and vessel remodelling. Model predictions confirm that small-molecule drug delivery is dominated by diffusive transport and further predict that the time of treatment is important for low affinity but not high affinity cytotoxic drugs, the size of the vessel wall pores plays an important role in the effect of low affinity but not high affinity drugs, that high affinity cytotoxic drugs remodel the tumour vasculature providing a large window for the normalisation of the vascular architecture, and that the combination of large pores and high affinity enhances cytotoxic drug delivery efficiency. These results have implications for treatment planning and methods to enhance drug delivery, and highlight the importance of in-silico modelling in investigating the optimisation of cancer therapy on a personalised setting. Public Library of Science 2018-10-08 /pmc/articles/PMC6193741/ /pubmed/30296260 http://dx.doi.org/10.1371/journal.pcbi.1006460 Text en © 2018 Vavourakis et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Vavourakis, Vasileios Stylianopoulos, Triantafyllos Wijeratne, Peter A. In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability |
title | In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability |
title_full | In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability |
title_fullStr | In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability |
title_full_unstemmed | In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability |
title_short | In-silico dynamic analysis of cytotoxic drug administration to solid tumours: Effect of binding affinity and vessel permeability |
title_sort | in-silico dynamic analysis of cytotoxic drug administration to solid tumours: effect of binding affinity and vessel permeability |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193741/ https://www.ncbi.nlm.nih.gov/pubmed/30296260 http://dx.doi.org/10.1371/journal.pcbi.1006460 |
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