Accessing the pharmacokinetics of magnetic nanoparticles in cirrhosis-associated hepatocarcinogenesis by ordinary differential equation modeling and AC biosusceptometry

Abstract

Pharmacokinetic studies using mathematical modeling examine the distribution of substances in multiple organs and compartments over time. Accordingly, this paper investigates the effect of cirrhosis-associated hepatocarcinogenesis on the pharmacokinetics of magnetic nanoparticles (MNPs) by using an in vivo model of cancer progression. To this end, a multichannel AC biosusceptometry system was used to record the transit of MNPs, in the heart and the liver, in two groups of animals: control (SAL), and within the diethylnitrosamine/thioacetamide-induced model of hepatocarcinogenesis (DEN/TAA). The evolution of MNPs concentration is then robustly described as a compartmental model, considering the transfer rate of nanoparticles from the heart to the liver (k1), their return from the liver to the heart through the circulatory system (k2), and their irreversible uptake by Kupffer cells within a liver subcompartment (k3). Our nonlinear mixed-effects parameter estimation modeling shows that k2 and k3 change between SAL and DEN/TAA groups, but not k1, indicating that cirrhosis-associated hepatocarcinogenesis is likely to affect mainly liver pharmacokinetics. Correspondingly, this is precisely reported here by also presenting a covariance analysis and an inter-individual variation of the transfer rates of the magnetic nanoparticles, contributing to their development in theranostic applications and tailored drug delivery systems.