Biodistribution and Physiologically-Based Pharmacokinetic Modeling of Gold Nanoparticles in Mice with Interspecies Extrapolation

Abstract

Gold nanoparticles (AuNPs) are a focus of growing medical research applications due to their unique chemical, electrical and optical properties. Because of uncertain toxicity, “green” synthesis methods are emerging, using plant extracts to improve biological and environmental compatibility. Here we explore the biodistribution of green AuNPs in mice and prepare a physiologically-based pharmacokinetic (PBPK) model to guide interspecies extrapolation. Monodisperse AuNPs were synthesized and capped with epigallocatechin gallate (EGCG) and curcumin. 64 CD-1 mice received the AuNPs by intraperitoneal injection. To assess biodistribution, groups of six mice were sacrificed at 1, 7, 14, 28 and 56 days, and their organs were analyzed for gold content using inductively coupled plasma mass spectrometry (ICP-MS). A physiologically-based pharmacokinetic (PBPK) model was developed to describe the biodistribution data in mice. To assess the potential for interspecies extrapolation, organism-specific parameters in the model were adapted to represent rats, and the rat PBPK model was subsequently evaluated with PK data for citrate-capped AuNPs from literature. The liver and spleen displayed strong uptake, and the PBPK model suggested that extravasation and phagocytosis were key drivers. Organ predictions following interspecies extrapolation were successful for rats receiving citrate-capped AuNPs. This work lays the foundation for the pre-clinical extrapolation of the pharmacokinetics of AuNPs from mice to larger species.

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

“…Furthermore, the base model for large molecules and therapeutic proteins in PK‐Sim does not explicitly include a hematopoietic cell compartment in addition to a vascular endothelial cell compartment, such as in the models put forward by Li and Balthasar or Aborig et al . Instead, the impacts of cellular uptake by vascular endothelial cells and hematopoietic cells are lumped together into 1 endosomal compartment.…”

“…Instead, the impacts of cellular uptake by vascular endothelial cells and hematopoietic cells are lumped together into 1 endosomal compartment. To correctly account for the ontogeny of this cell population, we have split the relative contributions to cellular uptake equally between vascular endothelium and hematopoietic cells in the absence of specific data, though this fraction may vary among specific organs (eg, spleen, where macrophages make up 30% of the cell content).…”

“…Furthermore, the base model for large molecules and therapeutic proteins in PK-Sim does not explicitly include a hematopoietic cell compartment in addition to a vascular endothelial cell compartment, such as in the models put forward by Li and Balthasar 60 or Aborig et al 67 Instead, the impacts of cellular uptake by vascular endothelial cells and hematopoietic cells are lumped together into 1 endosomal compartment. To correctly account for the ontogeny of this cell population, we have split the relative contributions to cellular uptake equally between vascular endothelium and hematopoietic cells in the absence of specific data, though this fraction may vary among specific organs (eg, spleen, where macrophages make up 30% of the cell content 67 ).…”

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles

“…Different pharmacokinetic models such as compartmental and especially physiologically based pharmacokinetic (PBPK) models have been developed to characterize the disposition of drugs in different organs and tissues, and especially in the liver, when they are administered in different types of nanoparticles (98,(106)(107)(108)(109)(110)(111)(112).…”

Tailored Gold Nanoparticles for Cancer Imaging and Therapy

“…However, AuNP can exhibit a cytotoxic profile, when the size of the nanoparticles is below 2 nm (ultrasmall AuNP) or when the stabilizing ligands determine a direct interaction with biomolecules or for catalytic activity of the unshielded gold surface. It has been reported that these ultrasmall AuNPs exhibit significantly different biodistribution and enhanced circulation times compared to larger AuNPs [81][82][83][84][85].…”