Mathematical Modeling and Experimental Validation of Extracellular Vesicle-Mediated Tumor Suppressor MicroRNA Delivery and Propagation in Ovarian Cancer Cells.

Abstract

Extracellular vesicle (EV)-mediated microRNA transfer and propagation from the donor cell to the recipient cell in the tumor microenvironment have significant implications, including the development of multidrug resistance (MDR). Although miRNA-encapsulated EV have been shown to have functional effects on recipient cells, the quantitative aspects of transfer kinetics and functional effects remain poorly understood. Intracellular events such as degradation of miRNA, loading of miRNA into EVs, cellular release of EVs, and their uptake by recipient cells govern the transfer and functional effect of encapsulated miRNA. Based on these rate-limiting steps, we developed a mathematical model using ordinary differential equations (model 1). We performed coculture experiments using ID8-VEGF ovarian cancer cells to demonstrate EV-mediated propagation of tumor suppressor miRNA Let7b administered with hyaluronic acid-poly(ethyleneimine) (HA-PEI) nanoparticles. Using the experimental data and model fitting, we determined the rate constants for the kinetic events involved in the transfer from the donor cells to the recipient cells. In model 2, we performed Let7b transfection experiments in ID8-VEGF cells with HA-PEI nanoparticles to determine the concentration-effect relationship on HMGA2 mRNA levels. Lastly, in model 3, we combined model 1 and model 2 parameters to describe the kinetics and effect relationship of EV-Let7b in recipient cells to predict the minimum number of miRNA copies needed to show functional effects.