Boolean network and meshless simulations for the comparison of transport and reaction mechanisms arising in one-short tri-exponential and uniform infusion electrochemotherapeutic treatments.

Drug administration via the bloodstream involves some transport and reaction mechanisms ( R T M s ), such as extravasation, perfusion along blood vessels, transmembrane and interstitial transport, protein dissociation and association, and lymphatic drainage. These R T M s can be influenced by the type of pharmacokinetic ( P K ) profile used for drug delivery in the circulatory system, as well as by the bloodstream velocity λ i n l . In electroporated tissues, the electric field magnitude ( E ) can also affect the R T M s because it brings about vessel vasoconstriction, cell membrane and vessel wall electro-permeabilization, and changes in tissue porosity. In the present work, in-house computational tools are employed to examine how the combination of E and λ i n l influences the R T M ' s existence, interaction, and rates arising in electrochemotherapy for two different P K s : One-short tri-exponential ( T P K ), where the drug concentration decreases exponentially after a one-short infusion, and one uniform ( U P K ), where the drug concentration is kept constant during the whole treatment. First, the ratios between extracellular, free intracellular, and bound intracellular concentrations are obtained from numerical simulations with a meshless code previously developed, calibrated, and validated. Subsequently, the interaction between the R T M s is investigated by means of a Boolean model presented here that is based on the comparison of the spatio-temporal evolution of the concentration ratios. Several combinations of E ( 0   k V / m ; 46   k V / m ; 70   k V / m ), λ i n l ( 1 × 10 - 4 m / s ; 1 × 10 - 3 m / s ; 1 × 10 - 2 m / s ), and P K ( T P K and U P K ) are tested. The in silico findings indicate that R T M ' s existence, interaction, and rates can vary between the two P K s ( T P K and U P K ) for a specific permutation of E and λ i n l . Nevertheless, common features are identified between these pharmacokinetic profiles. In general, the lower E , the more uniform the transmembrane transport in the radial and axial direction; the decrease of λ i n l also improves the radial homogeneity of this transport mechanism but negatively influences the axial uniformity. The uniformity of the mechanisms of association and dissociation is only altered monotonously by E (Vélez Salazar and Patiño Arcila, 2025).