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.
Highlights
Nanotechnology engineering can be defined as the engineering of matter at the nanoscale
One of the most promising nanomaterials being researched for biomedical applications is the gold nanoparticle (AuNP)
It is important to consider the pharmacokinetics (PK) of NPs during pre-clinical development for biomedical applications, in order to ascertain the likelihood of achieving sufficient exposure in tissues of interest, while minimizing systemic toxicity
Summary
Nanotechnology engineering can be defined as the engineering of matter at the nanoscale. Since that time there have been very few successful translations of AuNPs to humans as a therapeutic agent [11] Part of this challenge is due to uncertainty about the biodistribution, pharmacokinetics and toxicity of AuNPs. It is important to consider the pharmacokinetics (PK) of NPs during pre-clinical development for biomedical applications, in order to ascertain the likelihood of achieving sufficient exposure in tissues of interest, while minimizing systemic toxicity. In contrast to traditional small molecule drugs, most NPs exhibit complex PK in vivo due to a variety of physicochemical and biological factors The uncertainties in these factors limit pre-clinical assessments, especially when extrapolating PK between routes of administration, or between species (e.g., mouse to rat or monkey to human) [12]. We integrate experimental techniques with an in silico approach to the biodistribution of AuNPs in mice to maximize learning, and set the stage for interspecies extrapolation in the pre-clinical development of AuNPs as a drug product
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