Electromotive Enhanced Drug Administration in Oncology: Principles, Evidence, Current and Emerging Applications

Abstract

Local-regional administration of cytotoxic drugs is an important adjunct to systemic chemotherapy amongst cancer patients. It allows for targeted delivery of agents at high concentration to target sites while minimizing systemic side effects. Despite the pharmacokinetic advantages of the local-regional approach, drug transport into tumor nodules remains limited due to the biophysical properties of these tissues. Electromotive enhanced drug administration (EMDA) represents a potential solution to overcome challenges in local drug transport by applying electric currents. Through electrokinetic phenomena of electromigration, electroosmosis and electroporation, electric currents have been shown to improve drug penetration and distribution in a wide variety of clinical applications. Amongst patients with non-muscular invasive bladder cancer (NMIBC) and basal and squamous cell skin cancers, EMDA has been successfully adopted and proven efficacious in several pre-clinical and clinical studies. Its application in ophthalmological and other conditions has also been explored. This review provides an overview of the underlying principles and factors that govern EMDA and discusses its application in cancer patients. We also discuss novel EMDA approaches in pre-clinical studies and explore future opportunities of developments in this field.

Keywords: drug transport; electric-driven; electromotive; electroporation; iontophoresis.

Figure 1

Electromotive drug administration (EMDA) encompasses the electrokinetic phenomena of electromigration (EM), electroosmosis (EO) and electroporation (EP). Conventionally, iontophoresis alone was commonly used to describe electric-driven drug transport.

Figure 2

Schematic diagram of an iontophoretic device consisting of a current source and two Ag|AgCl electrodes. During EMDA, D+ is placed inside the electrode compartment bearing the same charge (i.e., the anode). Cations, including D+, are transported from the anode into the skin. At the same time, anions from the skin move into the anode. In the cathode, anions leave the cathode towards the skin, while cations move into the cathode.

Figure 3

Schematic depiction of EMDA of a cationic drug molecule (+) within a filled bladder. The foley catheter contains a spiral Ag electrode at its tip and is connected to a current generator. During EMDA, grounding skin electrodes are placed over the anterior abdominal wall and connected to the cathode component of the generator.

Figure 4

Schematic overview of electrostatic precipitation combined with pressurized intraperitoneal aerosol chemotherapy (e-PIPAC) where electromotive forces are used to improve IP drug distribution and penetration. (Adapted from Rahimi-Gorji et al., 2020).

Figure 5

(A) Schema of in vitro IP model: custom-made plastic cylinder that mimics the abdominal cavity. A Physionizer^® Mini 30N2 current generator is connected to a Foley catheter housing a silver spiral electrode and a grounding metallic plate. The setup aims to replicate the delivery of IP therapeutics. (B) Confocal microscopy images of porcine peritoneum tissue treated with fluorescent nanoparticles before (top) and after (bottom) EMDA, demonstrating improved penetration after EMDA. Experimental surgery lab, Ghent University, unpublished data.