Tampa, FL (Scicasts) — Researchers have combined single-cell imaging of cancer cells in mice with mathematical modelling to determine which drug characteristics are the most important for efficient drug uptake.

Drug therapies that target a specific molecule have changed the way patients are treated for cancer and greatly improved survival rates. However, some patients do not respond to these therapies because the drug is not reaching the tumour cells effectively.  

One of the inherent problems with targeted therapies is that tumours and their surrounding environment are complex and heterogeneous. Not all cells in a given tumour are alike. They can differ from one another in the expression of the targeted membrane receptors which may result in inadequate uptake and non-uniform response to the targeting drug. Additionally, the surrounding tumour environment is composed of different cell types with different properties and densities that can impact the ability of a drug to be effective. 

These variations make it difficult to develop drugs that can effectively target all of the cells in a tumour. Furthermore, these cellular and genetic differences may cause a patient to be unresponsive to a cancer-targeted drug because some tumour cells may not be fully exposed to the drug and this incomplete exposure may enable these cells to develop drug resistance. 

"Clinical success or failure of targeted therapy depends heavily on whether the drug molecules are able to reach all tumour cells and engage with their molecular targets to invoke the desired therapeutic effect," said Dr. Kasia A. Rejniak, associate member of the Department of Integrated Mathematical Oncology at Moffitt. This work was accomplished through collaboration between Rejniak computational group and the laboratory group of Dr. Dave L. Morse, associate member of the Department of Cancer Physiology.

The standard methods that scientists use to study drug uptake are based on the idea that a tumour and its surroundings have uniform characteristics. However, this assumption is inaccurate and may lead to a one-size-fits-all approach to treatment. The Moffitt research team wanted to take a different approach to study drug uptake. They used mathematical modelling and imaging techniques that allowed them to track and predict the ability of a single cell to take up a drug. Within their model, they compared different drug characteristics and tumour properties to determine which conditions lead to more effective drug uptake by a cell.

They discovered that the amount of drug that binds to a cell depends on how quickly a drug diffused through the tissue rather than on the concentration of drug that enters the tissue. Drugs that diffused quickly tended to bind more effectively to cells that were further away from blood vessels. Alternatively, drugs that diffused slowly tended to bind to cells that were closer to blood vessels and were more effective when the cells were tightly packed. The researchers also showed that drugs that are released quickly are able to bind more effectively to cells with different levels of drug receptors. 

Spatial distribution of ligand molecules within the tissue and inside the cells after receptor internalization at the same three time points. Images were rendered to represent fluorescence intensity of ligand concentration. For each case (n = 3) three simulations were performed, and the average values are shown. All s.d. values were smaller than 5% and were not shown for clarity of images.

These discoveries suggest that changing different properties of a drug or the way a drug is administered may lead to increased delivery to tumour cells. "For example, to treat the fast-growing cells located near the vasculature, slowly diffusing agents may be beneficial. In contrast, for the dormant cells in poorly vascularized regions, the highly mobile agents may be preferential, or in some cancers, local injection directly to the tumour site may be beneficial," explained Rejniak. Ultimately, the researchers hope that their approach could eventually be used to design more personalized treatment options for cancer patients.

Article adapted from a H. Lee Moffitt Cancer Center & Research Institute news release.

Publication: Targeting Ligand Specificity Linked to Tumour Tissue Topological Heterogeneity via Single-Cell Micro-Pharmacological Modelling. Karolak, A et al. Scientific Reports (February 26, 2018): Click here to view.