Feasibility and efficacy of electromotive intraperitoneal drug delivery: A hybrid study

Intraperitoneal drug delivery (IPDD) is increasingly used to treat peritoneal metastases (PM). However, the adverse biomechanical properties of tumor tissue, such as elevated interstitial fluid pressure and matrix stiffness, are known to impede the transport and efficacy of small-molecule anticancer drugs and nanoparticles (NPs). Physical methods may enhance tissue penetration after IPDD treatment. In this study, we explored the use of an electrical direct current (DC) field generated by electromotive drug administration (EMDA) as a novel physical method to enhance tissue penetration after IPDD. This method involves the combination of a fluid column with a pulsed DC current. A novel in vitro setup was developed in combination with a computational fluid dynamics (CFD) model to test the effects of different treatment variables on the penetration of 100 and 200 nm positively charged NPs in healthy porcine peritoneal samples. We found that tissue penetration using EMDA improved with increasing current intensity, higher temperature of the carrier fluid, and longer administration time, with a plateau reached at 30 min. Isotonic carrier fluids performed better compared to hypotonic and hypertonic solutions. Using these optimized parameters, in vivo studies were performed in both healthy and tumor-induced rats, where peritoneal tissues from all animals and tumor samples from the tumor-induced group were evaluated. EMDA was well tolerated and resulted in significantly enhanced penetration of 100 nm NPs, achieving deeper and more uniform distribution within healthy peritoneum and tumor nodules, irrespective of the anatomical location. These findings highlight EMDA as a promising approach to overcome intrinsic transport barriers of PM and underscore its potential to improve the efficacy of intraperitoneal NP-based therapy for peritoneal metastases.