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

Scientific Reports
Aleksandra KarolakKatarzyna A Rejniak

Abstract

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 indivi...Continue Reading

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Citations

Dec 21, 2018·PLoS Computational Biology·Vlad ElgartJoseph Loscalzo
Jun 5, 2020·Bulletin of Mathematical Biology·Catherine BerrouetNecibe Tuncer

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Methods Mentioned

BETA
imaging techniques
xenograft
fluorescence
xenografts
fluorescence microscopy
biopsy

Software Mentioned

GraphPad Prism
ASW
FV10

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