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The use of nanobiomaterials (NBMs) is becoming increasingly popular in the field of medicine. To improve the understanding on the biodistribution of NBMs, the present study aimed to implement and parametrize a physiologically based pharmacokinetic (PBPK) model. This model was used to describe the biodistribution of two NBMs after intravenous administration in rats, namely, poly(alkyl cyanoacrylate) (PACA) loaded with cabazitaxel (PACA-Cbz), and LipImage™ 815. A Bayesian parameter estimation approach was applied to parametrize the PBPK model using the biodistribution data. Parametrization was performed for two distinct dose groups of PACA-Cbz. Furthermore, parametrizations were performed three distinct dose groups of LipImage™ 815, resulting in a total of five different parametrizations. The results of this study indicate that the PBPK model can be adequately parametrized using biodistribution data. The PBPK parameters estimated for PACA-Cbz, specifically the vascular permeability, the partition coefficient, and the renal clearance rate, substantially differed from those of LipImage™ 815. This emphasizes the presence of kinetic differences between the different formulations and substances and the need of tailoring the parametrization of PBPK models to the NBMs of interest. The kinetic parameters estimated in this study may help to establish a foundation for a more comprehensive database on NBM-specific kinetic information, which is a first, necessary step towards predictive biodistribution modeling. This effort should be supported by the development of robust in vitro methods to quantify kinetic parameters. Graphical abstract

Mesenchymal stromal cells (MSCs) administered intravenously (IV) have shown efficacy in pre-clinical models of various diseases. This is despite the cells not reaching the site of injury due to entrapment in the lungs. The ability of MSCs to modulate immune responses has been proposed as one of the mechanisms by which these cells provide therapeutic benefits, irrespective of whether they are sourced from bone marrow, adipose tissue or umbilical cord. To better understand how MSCs affect innate immune cell populations in the lung, we evaluated the percentage, distribution and phenotype of neutrophils, monocytes and macrophages by flow cytometry and histological analyses after delivering human umbilical cord-derived MSCs (hUC-MSCs) IV into immunocompetent mice. After 2 h, we observed a sharp increase in neutrophils, and pro-inflammatory monocytes and macrophages. Moreover, these immune cells localised in the vicinity of the MSCs suggesting an active role in their clearance. By 24 h, we detected an increase in anti-inflammatory monocytes and macrophages. These results suggest that the IV injection of hUC-MSCs leads to an initial inflammatory phase in the lung shortly after injection, followed by a resolution phase 24 h later.