Blood flow modifying and vascular-disrupting effects of electroporation and electrochemotherapy

Abstract

Electroporation/electropermeabilization (EP), achieved by application of electric pulses to cells or tissues, induces reversible permeabilization of cell membranes under suitable conditions, thus facilitating entry of exogenous molecules into cells. EP of tissues in humans is feasible, efficient, and tolerable, and its most advanced routine clinical use is electrochemotherapy (ECT), where cytotoxic drugs are delivered to cells to treat tumors. It is increasingly used in different tumor types, and the technology is being adopted for the treatment of deep-seated tumors like liver, pancreas, and bone metastases and colon tumors. Although the primary mode of action of ECT is the destruction of tumor cells due to the increased cytotoxicity of chemotherapeutic drugs, it also has different effects on the tissue level. It was shown that EP and ECT have blood flow-modifying effects on normal as well as on tumor vasculature. Application of EP pulses to normal blood vessels increases the permeability of affected blood vessels; causes a transient vascular lock, i.e., decrease in perfusion; and modulates the diameter of affected blood vessels. Similarly, in tumors, application of EP or ECT increases the permeability of affected blood vessels and causes a vascular lock. In case of normal blood vessels, these effects are short lived, whereas in case of tumor bloodvessels, the effects are long lasting and resolve more than 24 h after ECT. Moreover, ECT has a direct cytotoxic effect on tumor endothelial cells; thus it has a vascular-disrupting effect. This effect is differential, destroying only tumor blood vessels and retaining the functionality of normal blood vessels surrounding the tumor, which is important when ECT is used in well-perfused organs such as the liver.