Connecting thein vitroandin vivoexperiments in electrochemotherapy - a feasibility study modeling cisplatin transport in mouse melanoma using the dual-porosity model

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Abstract

In electrochemotherapy two conditions have to be met to be successful – the electric field of sufficient amplitude and sufficient uptake of chemotherapeutics in the tumor. Current treatment plans only take into account critical electric field to achieve cell membrane permeabilization. However, permeabilization alone does not guarantee uptake of chemotherapeutics and consequently successful treatment. We performed a feasibility study to determine whether the transport of cisplatin in vivo could be calculated based on experiments performed in vitro. In vitro, a spectrum of parameters can be explored without ethical issues. Mouse melanoma B16-F1 cell suspension and inoculated B16-F10 tumors were exposed to electric pulses in the presence of chemotherapeutic cisplatin. The uptake of cisplatin was measured by inductively coupled plasma mass spectrometry. We modeled the transport of cisplatin with the dual-porosity model, which is based on the diffusion equation, connects pore formation with membrane permeability, and includes transport between several compartments. In our case, there were three compartments - tumor cells, interstitial fraction and peritumoral region. Our hypothesis was that in vitro permeability coefficient could be introduced in vivo, as long as tumor physiology was taken into account. Our hypothesis was confirmed as the connection of in vitro and in vivo experiments was possible by introducing a transformation coefficient which took into account the in vivo characteristics, i.e., smaller available area of the plasma membrane for transport due to cell density, presence of cell-matrix in vivo, and reduced drug mobility. We thus show that it is possible to connect in vitro and in vivo experiments of electrochemotherapy. However, more experimental work is required for model validation.

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