ABSTRACT
Blood vessels, the extracellular space, and the cell membrane represent physiologic barriers to nanoparticle-based drug delivery for cancer therapy. We demonstrate that electroporation (EP) can assist in the delivery of dye stabilized sorafenib nanoparticles (SFB-IR783) by increasing the permeability of endothelial monolayers, improving diffusion through the extracellular space in tumorspheres, and by disrupting plasma membrane function in cancer cells. These changes occur in a dose-dependent fashion, increasing proportionally with electric field strength. Cell death from irreversible electroporation (IRE) was observed to contribute to the persistent transport of SFB-IR783 through these physiologic barriers. In a model of mice bearing bilateral xenograft HCT116 colorectal tumors, treatment with EP resulted in the immediate and increased uptake of SFB-IR783 when compared with the untreated contralateral tumor. The uptake of SFB-IR783 was independent of direct transfection of cells through EP and was mediated by changes in vascular permeability and extracellular diffusion. The combination of EP and SFB-IR783 was observed to result in 40% reduction in mean tumor diameter when compared with sham treatment (pâ¯<â¯.05) at the time of sacrifice, which was not observed in cohorts treated with EP alone or SFB-IR783 alone. Treatment of tumor with EP can augment the uptake and increase the efficacy of nanoparticle therapy.
