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

Projektbeschreibung

Elektroporation der biologischen Zellmembran durch Behandlung mit gepulsten elektrischen Feldern

Die Integrität der Zellmembran wirkt wie eine Barriere. Um therapeutische Moleküle in die Zelle abzugeben, muss diese Barriere vorübergehend ausgehebelt werden. Gepulste elektrische Hochspannungsfelder kommen in der Medizin immer häufiger zum Einsatz, um die Zellmembran durch die sogenannte Zellmembran-Elektroporation durchlässig zu machen. Zu den klinischen Anwendungen auf Basis gepulster elektrischer Felder zählen verschiedene gentherapeutische Verfahren, DNS-Impfung, Elektrochemotherapie, die nicht-thermische Tumorablation und die kardiale Ablation. Das EU-finanzierte Projekt EPmIC zielt darauf ab, einen Ansatz zu entwickeln, mit dem sich die Ansprechbarkeit einer Zelle für die Behandlung mit gepulsten elektrischen Feldern auf kontrollierte und klinisch anwendbare Weise steigern oder verringern lässt. Dieser Ansatz soll auf dem Einsatz von Membranionenkanälen basieren, die das Ausmaß und die Lebensdauer der Membrandepolarisation nach der Impulsabgabe, einem wichtigen Merkmal der Membranelektroporation, beeinflussen können.

Ziel

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.