Physiologically based pharmacokinetic modeling of polyethylene glycol-coated polyacrylamide nanoparticles in rats

Abstract

Nanoparticles' health risks depend on their biodistribution in the body. Phagocytosis may greatly affect this distribution but has not yet explicitly accounted for in whole body pharmacokinetic models. Here, we present a physiologically based pharmacokinetic model that includes phagocytosis of nanoparticles to explore the biodistribution of intravenously injected polyethylene glycol-coated polyacrylamide nanoparticles in rats. The model explains 97% of the observed variation in nanoparticles amounts across organs. According to the model, phagocytizing cells quickly capture nanoparticles until their saturation and thereby constitute a major reservoir in richly perfused organs (spleen, liver, bone marrow, lungs, heart and kidneys), storing 83% of the nanoparticles found in these organs 120 h after injection. Key determinants of the nanoparticles biodistribution are the uptake capacities of phagocytizing cells in organs, the partitioning between tissue and blood, and the permeability between capillary blood and tissues. This framework can be extended to other types of nanoparticles by adapting these determinants.

Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles

“…24 In brief, this model involves ten compartments, each divided into subcompartments of blood, tissue, and PCs ( Figure 1). The physiological parameters (Table 2) were from the same as those used by Li et al 24 The following assumptions and modifications of the model were made.…”

“…as in the Li model, that is, all organs other than brain were assigned a high coefficient of permeability (X fast ) and carcass (X rest ) assumed to exhibit a medium permeability. 24 In the second set, X fast was reserved for liver and spleen, whereas bone marrow, heart, lung, and kidney were assigned X rest . These assignments were based on the fact that the PCs in liver and spleen are in direct contact with blood to a much greater extent than those in other compartments.…”

“…In the case of PAA-PEG, the parameters reported by Li et al were used as the initial values. 24 The model was then run simultaneously with the data sets for all four NPs employing the same number of PCs in each tissue, N tissue , in all four cases. The NP-specific parameters optimized were as follows: the clearance to feces (rate of clearance in feces [CL f ]) and urine (rate of clearance in urine [CL u ]), the rates of uptake by PCs in the spleen (rate constant for uptake by PCs in the spleen [k sab0 ]) and other organs (rate constant for uptake by PCs [k ab0 ]), the blood:tissue partition coefficient (P), maximal uptake per PC (M capi ), and the three coefficients for permeability between blood and tissues (X fast , X rest , and X brain ).…”

“…24,29 Here, we also incorporate data concerning uncoated polyacrylamide (PAA), gold, and titanium dioxide (TiO 2 ) NPs administered intravenously to rats.…”

Physiologically based pharmacokinetic modeling of zinc oxide nanoparticles and zinc nitrate in mice

“…According to previous study, phagocytizing cells rapidly capture NPs until their saturation, constitute a major reservoir in richly perfused organs, including the spleen, liver, bone marrow, lungs, heart, and kidneys, and store 83% NPs in these organs 120 hours after injection. 39 To more comprehensively understand the role of the mononuclear phagocytic system in the biodistribution of NPs, we will include mononuclear phagocytic system subcompartments in these organs when we construct PBPK models for NPs in future studies.…”