Tissue electroporation: Quantification and analysis of heterogeneous transport in multicellular environments

Although electroporation is gaining increased attention as a technology to enhance clinical chemotherapy and gene therapy of tissues, direct measurements of electroporation-mediated transport in multicellular environments are lacking. In this study, we used multicellular tumor spheroids of DU145 prostate cancer cells as a model tissue to measure the levels and distribution of molecular uptake in a multicellular environment as a function of electrical and other parameters. These measurements, and subsequent analysis, were used to test the hypothesis that cells in a multicellular environment respond to electroporation in a heterogeneous manner that differs from isolated cells in suspension due to differences in cell state, local solute concentration, and local electric field. In support of the hypothesis, molecular uptake was consistently lower for cells within spheroids than cells in dilute suspension and was spatially heterogeneous, with progressively less uptake observed for cells located deeper within spheroid interiors. Reduced uptake and heterogeneity can be explained quantitatively by accounting for the effects of cell size on transmembrane voltage and cell volume, limited extracellular solute reservoir, heterogeneous field strength due to influence of neighboring cells, and diffusional lag times.