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Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling

Targeted therapy has held promise to be a successful anticancer treatment due to its specificity towards tumor cells that express the target receptors. However, not all targeting drugs used in the clinic are equally effective in tumor eradication. To examine which biochemical and biophysical propert...

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Autores principales: Karolak, Aleksandra, Estrella, Veronica C., Huynh, Amanda S., Chen, Tingan, Vagner, Josef, Morse, David L., Rejniak, Katarzyna A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827036/
https://www.ncbi.nlm.nih.gov/pubmed/29483578
http://dx.doi.org/10.1038/s41598-018-21883-z
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author Karolak, Aleksandra
Estrella, Veronica C.
Huynh, Amanda S.
Chen, Tingan
Vagner, Josef
Morse, David L.
Rejniak, Katarzyna A.
author_facet Karolak, Aleksandra
Estrella, Veronica C.
Huynh, Amanda S.
Chen, Tingan
Vagner, Josef
Morse, David L.
Rejniak, Katarzyna A.
author_sort Karolak, Aleksandra
collection PubMed
description Targeted therapy has held promise to be a successful anticancer treatment due to its specificity towards tumor cells that express the target receptors. However, not all targeting drugs used in the clinic are equally effective in tumor eradication. To examine which biochemical and biophysical properties of targeted agents are pivotal for their effective distribution inside the tumor and their efficient cellular uptake, we combine mathematical micro-pharmacological modeling with in vivo imaging of targeted human xenograft tumors in SCID mice. The mathematical model calibrated to experimental data was used to explore properties of the targeting ligand (diffusion and affinity) and ligand release schemes (rates and concentrations) with a goal to identify the properties of cells and ligands that enable high receptor saturation. By accounting for heterogeneities typical of in vivo tumors, our model was able to identify cell- and tissue-level barriers to efficient drug uptake. This work provides a base for utilizing experimentally measurable properties of a ligand-targeted agent and patient-specific attributes of the tumor tissue to support the development of novel targeted imaging agents and for improvement in their delivery to individual tumor cells.
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spelling pubmed-58270362018-03-01 Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling Karolak, Aleksandra Estrella, Veronica C. Huynh, Amanda S. Chen, Tingan Vagner, Josef Morse, David L. Rejniak, Katarzyna A. Sci Rep Article Targeted therapy has held promise to be a successful anticancer treatment due to its specificity towards tumor cells that express the target receptors. However, not all targeting drugs used in the clinic are equally effective in tumor eradication. To examine which biochemical and biophysical properties of targeted agents are pivotal for their effective distribution inside the tumor and their efficient cellular uptake, we combine mathematical micro-pharmacological modeling with in vivo imaging of targeted human xenograft tumors in SCID mice. The mathematical model calibrated to experimental data was used to explore properties of the targeting ligand (diffusion and affinity) and ligand release schemes (rates and concentrations) with a goal to identify the properties of cells and ligands that enable high receptor saturation. By accounting for heterogeneities typical of in vivo tumors, our model was able to identify cell- and tissue-level barriers to efficient drug uptake. This work provides a base for utilizing experimentally measurable properties of a ligand-targeted agent and patient-specific attributes of the tumor tissue to support the development of novel targeted imaging agents and for improvement in their delivery to individual tumor cells. Nature Publishing Group UK 2018-02-26 /pmc/articles/PMC5827036/ /pubmed/29483578 http://dx.doi.org/10.1038/s41598-018-21883-z Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Karolak, Aleksandra
Estrella, Veronica C.
Huynh, Amanda S.
Chen, Tingan
Vagner, Josef
Morse, David L.
Rejniak, Katarzyna A.
Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling
title Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling
title_full Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling
title_fullStr Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling
title_full_unstemmed Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling
title_short Targeting Ligand Specificity Linked to Tumor Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modeling
title_sort targeting ligand specificity linked to tumor tissue topological heterogeneity via single-cell micro-pharmacological modeling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827036/
https://www.ncbi.nlm.nih.gov/pubmed/29483578
http://dx.doi.org/10.1038/s41598-018-21883-z
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