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Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill
It has been hypothesized that continuously releasing drug molecules into the tumor over an extended period of time may significantly improve the chemotherapeutic efficacy by overcoming physical transport limitations of conventional bolus drug treatment. In this paper, we present a generalized space-...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902302/ https://www.ncbi.nlm.nih.gov/pubmed/27286441 http://dx.doi.org/10.1371/journal.pcbi.1004969 |
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author | Wang, Zhihui Kerketta, Romica Chuang, Yao-Li Dogra, Prashant Butner, Joseph D. Brocato, Terisse A. Day, Armin Xu, Rong Shen, Haifa Simbawa, Eman AL-Fhaid, A. S. Mahmoud, S. R. Curley, Steven A. Ferrari, Mauro Koay, Eugene J. Cristini, Vittorio |
author_facet | Wang, Zhihui Kerketta, Romica Chuang, Yao-Li Dogra, Prashant Butner, Joseph D. Brocato, Terisse A. Day, Armin Xu, Rong Shen, Haifa Simbawa, Eman AL-Fhaid, A. S. Mahmoud, S. R. Curley, Steven A. Ferrari, Mauro Koay, Eugene J. Cristini, Vittorio |
author_sort | Wang, Zhihui |
collection | PubMed |
description | It has been hypothesized that continuously releasing drug molecules into the tumor over an extended period of time may significantly improve the chemotherapeutic efficacy by overcoming physical transport limitations of conventional bolus drug treatment. In this paper, we present a generalized space- and time-dependent mathematical model of drug transport and drug-cell interactions to quantitatively formulate this hypothesis. Model parameters describe: perfusion and tissue architecture (blood volume fraction and blood vessel radius); diffusion penetration distance of drug (i.e., a function of tissue compactness and drug uptake rates by tumor cells); and cell death rates (as function of history of drug uptake). We performed preliminary testing and validation of the mathematical model using in vivo experiments with different drug delivery methods on a breast cancer mouse model. Experimental data demonstrated a 3-fold increase in response using nano-vectored drug vs. free drug delivery, in excellent quantitative agreement with the model predictions. Our model results implicate that therapeutically targeting blood volume fraction, e.g., through vascular normalization, would achieve a better outcome due to enhanced drug delivery. AUTHOR SUMMARY: Cancer treatment efficacy can be significantly enhanced through the elution of drug from nano-carriers that can temporarily stay in the tumor vasculature. Here we present a relatively simple yet powerful mathematical model that accounts for both spatial and temporal heterogeneities of drug dosing to help explain, examine, and prove this concept. We find that the delivery of systemic chemotherapy through a certain form of nano-carriers would have enhanced tumor kill by a factor of 2 to 4 over the standard therapy that the patients actually received. We also find that targeting blood volume fraction (a parameter of the model) through vascular normalization can achieve more effective drug delivery and tumor kill. More importantly, this model only requires a limited number of parameters which can all be readily assessed from standard clinical diagnostic measurements (e.g., histopathology and CT). This addresses an important challenge in current translational research and justifies further development of the model towards clinical translation. |
format | Online Article Text |
id | pubmed-4902302 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-49023022016-06-24 Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill Wang, Zhihui Kerketta, Romica Chuang, Yao-Li Dogra, Prashant Butner, Joseph D. Brocato, Terisse A. Day, Armin Xu, Rong Shen, Haifa Simbawa, Eman AL-Fhaid, A. S. Mahmoud, S. R. Curley, Steven A. Ferrari, Mauro Koay, Eugene J. Cristini, Vittorio PLoS Comput Biol Research Article It has been hypothesized that continuously releasing drug molecules into the tumor over an extended period of time may significantly improve the chemotherapeutic efficacy by overcoming physical transport limitations of conventional bolus drug treatment. In this paper, we present a generalized space- and time-dependent mathematical model of drug transport and drug-cell interactions to quantitatively formulate this hypothesis. Model parameters describe: perfusion and tissue architecture (blood volume fraction and blood vessel radius); diffusion penetration distance of drug (i.e., a function of tissue compactness and drug uptake rates by tumor cells); and cell death rates (as function of history of drug uptake). We performed preliminary testing and validation of the mathematical model using in vivo experiments with different drug delivery methods on a breast cancer mouse model. Experimental data demonstrated a 3-fold increase in response using nano-vectored drug vs. free drug delivery, in excellent quantitative agreement with the model predictions. Our model results implicate that therapeutically targeting blood volume fraction, e.g., through vascular normalization, would achieve a better outcome due to enhanced drug delivery. AUTHOR SUMMARY: Cancer treatment efficacy can be significantly enhanced through the elution of drug from nano-carriers that can temporarily stay in the tumor vasculature. Here we present a relatively simple yet powerful mathematical model that accounts for both spatial and temporal heterogeneities of drug dosing to help explain, examine, and prove this concept. We find that the delivery of systemic chemotherapy through a certain form of nano-carriers would have enhanced tumor kill by a factor of 2 to 4 over the standard therapy that the patients actually received. We also find that targeting blood volume fraction (a parameter of the model) through vascular normalization can achieve more effective drug delivery and tumor kill. More importantly, this model only requires a limited number of parameters which can all be readily assessed from standard clinical diagnostic measurements (e.g., histopathology and CT). This addresses an important challenge in current translational research and justifies further development of the model towards clinical translation. Public Library of Science 2016-06-10 /pmc/articles/PMC4902302/ /pubmed/27286441 http://dx.doi.org/10.1371/journal.pcbi.1004969 Text en © 2016 Wang 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 Wang, Zhihui Kerketta, Romica Chuang, Yao-Li Dogra, Prashant Butner, Joseph D. Brocato, Terisse A. Day, Armin Xu, Rong Shen, Haifa Simbawa, Eman AL-Fhaid, A. S. Mahmoud, S. R. Curley, Steven A. Ferrari, Mauro Koay, Eugene J. Cristini, Vittorio Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill |
title | Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill |
title_full | Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill |
title_fullStr | Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill |
title_full_unstemmed | Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill |
title_short | Theory and Experimental Validation of a Spatio-temporal Model of Chemotherapy Transport to Enhance Tumor Cell Kill |
title_sort | theory and experimental validation of a spatio-temporal model of chemotherapy transport to enhance tumor cell kill |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902302/ https://www.ncbi.nlm.nih.gov/pubmed/27286441 http://dx.doi.org/10.1371/journal.pcbi.1004969 |
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