A physiologically based pharmacokinetic model for polyethylene glycol-coated gold nanoparticles of different sizes in adult mice

Abstract

Nanoparticles (NPs) are widely used in various fields of nanomedicine. A systematic understanding of NP pharmacokinetics is crucial in their design, applications, and risk assessment. In order to integrate available experimental information and to gain insights into NP pharmacokinetics, a membrane-limited physiologically based pharmacokinetic (PBPK) model for polyethylene glycol-coated gold (Au) NPs (PEG-coated AuNPs) was developed in mice. The model described endocytosis of the NPs in the liver, spleen, kidneys, and lungs and was calibrated using data from mice that were intravenously injected with 0.85 mg/kg 13 nm and 100 nm PEG-coated AuNPs. The model adequately predicted multiple external datasets for PEG-coated AuNPs of similar sizes (13-20 nm; 80-100 nm), indicating reliable predictive capability in suitable size ranges. Simulation results suggest that endocytosis of NPs is time and size dependent, i.e. endocytosis of larger NPs occurs immediately and predominately from the blood, whereas smaller NPs can diffuse through the capillary wall and their endocytosis appears mainly from the tissue with a 10-h delay, which may be the primary mechanism responsible for the reported size-dependent pharmacokinetics of NPs. Several physiological parameters (e.g. liver weight fraction of body weight) were identified to have a high influence on selected key dose metrics, indicating the need for additional interspecies comparison and scaling studies and to conduct pharmacokinetic studies of NPs in species that are more closely related to humans in these parameters. This PBPK model provides useful insights into the size, time, and species dependence of NP pharmacokinetics.

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

“…59 In any case, most, if not all, investigators incorporate partition coefficients into their nano PBPK models. 10,[17][18][19][20][21][22][24][25][26][27] Here, we found that at least in the case of PAA-PEG, PAA, and gold NPs, the biokinetics cannot be accurately described without introducing a P factor and a similar conclusion was reached by Lin et al 25 The exchange of NPs between blood and organs is strongly influenced by the ability to cross the endothelium. This endothelial permeability varies between organs as a result of differences in the degree of fenestration, as well as phagocytic capacity.…”

“…In contrast, the model developed by Lin et al describes the rate of uptake as a function of time with the Hill equation. 25 On the other hand, the model developed by Bachler et al employs an uptake rate that is independent of both time and concentration, that is, with no saturation of the PCs. 23,28 The slower uptake for PAA-PEG than PAA into PCs was expected since the polyethylene glycol coating reduces the attachment of proteins and formation of corona, thereby attenuating and delaying recognition and uptake.…”

“…51,52 Although the nano PBPK models developed by Bachler et al and Lin et al also incorporate phagocytosis, their findings cannot be readily compared to our own because of major differences in the organs monitored, organs with/without PCs, PC saturation, translocation from blood to PCs (serial/ parallel), blood:tissue partitioning, and so on. 23,25,28 Several models for cellular NP uptake in vitro have been proposed, some of which suggest that the NPs are adsorbed to the cell surface prior to endocytosis. 16,[46][47][48] According to these models, the rate of this is faster than the rate of endocytosis, which depends on the accessibility and recirculation of appropriate receptors.…”

Mathematical modeling and simulation in animal health – Part II: principles, methods, applications, and value of physiologically based pharmacokinetic modeling in veterinary medicine and food safety assessment

“…The fat should also be selected as a single compartment for highly lipophilic compounds (Evans & Andersen, ). In the field of nanomaterial PBPK modeling, the liver, spleen, kidneys, and lungs are designated as individual compartments because they are major phagocytic organs where nanomaterials primarily accumulate (Bachler et al ., ; Lin et al ., ,b).…”

Intracellular imaging of quantum dots, gold, and iron oxide nanoparticles with associated endocytic pathways

“…Even though a decade of research formulating NP for molecular imaging obstacles still remain for clinical use due to the composition, agent stability, low specificity and safety concerns. Pharmacokinetic studies showed that metallic NP may be distributed in the body and accumulate in different organs and retain within the body for more than six months based on their size . In addition, a detailed review summarized that metallic NP may cross the blood–brain barrier and even the placenta .…”