Controlling the susceptibility of biological cells to pulsed electric field treatment by using ion channel modulators

Descripción del proyecto

Electroporación de la membrana celular biológica mediante un tratamiento de campo eléctrico pulsado

La integridad de la membrana celular presenta una barrera que debe romperse de manera transitoria para administrar moléculas terapéuticas en el interior de la célula. Los campos eléctricos de alta intensidad pulsados (PEF, por sus siglas en inglés) se utilizan cada vez más en medicina para lograr la permeabilidad de la membrana celular mediante un fenómeno conocido como electroporación de la membrana celular. Las aplicaciones clínicas basadas en PEF incluyen técnicas de genoterapia, vacunas de ADN, electroquimioterapia, ablación tumoral no térmica y ablación cardíaca. El proyecto financiado con fondos europeos EPmIC busca formular un método que permita aumentar o disminuir la susceptibilidad de las células al tratamiento de PEF de una manera controlada y con aplicación clínica. Su propuesta se basa en la aplicación de moduladores de los canales de iones de la membrana para influir sobre el alcance y la longevidad de la despolarización de la membrana pospulso asociada con la electroporación de la membrana.

Objetivo

The integrity of the cell membrane, while essential for life of any biological cell, presents a barrier that sometimes needs to be transiently disrupted in order to deliver therapeutic molecules inside the cell. High-intensity pulsed electric fields (PEFs) are used increasingly in medicine to achieve such increase in cell membrane permeability via a phenomenon called cell membrane electroporation. PEF-based clinical applications include gene therapy techniques, DNA vaccination, electrochemotherapy, non-thermal tumor ablation, and cardiac ablation. Depending on the desired outcome of the PEF treatment, the targeted cells must either survive or die. However, different cell types exhibit different susceptibility to PEF treatment, with some cells being killed at lower pulse amplitude than others, which often presents a disadvantage that limits the safety and efficiency of PEF treatment. In this action I aim to design an approach that will allow us to increase or decrease cell’s susceptibility to PEF treatment in a controlled, clinically applicable way. The approach is based on using modulators of membrane ion channels, that can influence the extent and longevity of post-pulse membrane depolarization – a hallmark of membrane electroporation. My idea is on the one hand inspired by increasing amount of evidence showing the involvement of ion channels in PEF-induced cell response, and on the other hand by the fact that ion channel modulators are already successfully used in treatment of various diseases and we can expect exciting development of new modulators in the near future. The design will be guided by state-of-the-art microscopic techniques and computational models, including molecular dynamics simulations, particle-based simulations, and finite element modeling, that will help elucidate the molecular mechanisms of membrane depolarization and choose the appropriate modulators and pulse parameters for fine-tuning the treatment outcome.