An assessment of the biodistribution, biopersistence and toxicity of gold nanoparticles

Abstract

The interest in biomedical applications of gold nanoparticles (AuNPs) has increased dramatically in the last decade due to their ease of synthesis, unique surface and optical properties. The main driver of this surge in research on potential biomedical applications which include inter alia; to photothermal therapy, diagnostic aids and drug delivery vehicles was their biocompatibility. Questions on the safety of AuNPs have resurfaced and justifiably due to the increase in the number of reports on their toxicity potential and toxicity. This whole debate on safety must be put to rest before biomedical applications of AuNPs can reach the clinic. Studies were designed to investigate the acute biodistribution, biopersistence, and bioaccumulation of AuNPs using a rodent model using male Sprague Dawley rats. In all the studies, toxicity endpoints were monitored. To fully understand the determinants of toxicity of AuNPs which are a multi-component system, the acute biodistribution of the gold core was determined simultaneously with that of the citrate coating using a novel dual radiolabeled technique. The amount of Au core and citrate surface coating was quantified using gamma spectroscopy and liquid scintillation respectively. The biopersistence was determined after a single intravenous injection over 56 days. The bioaccumulation was assessed over 56 days as well after intravenous administration of multiple (7) doses of AuNPs at 3 different dose levels. In both the biopersistence and bioaccumulation studies, toxicity endpoints were monitored using histopathological analysis of organs and assessment of markers of kidney (creatinine and blood nitrogen urea) and liver (alkaline phosphatase, alanine transferase and total bilirubin) damage. The amount of Au in the tissues was quantified using neutron activation analysis (NAA) in the biopersistence and bioaccumulation studies. The acute biodistribution pattern of the Au core was found to be different to that of the citrate surface coating. In the acute study, Au widely distributed to all the tissues with the highest amount in the liver, spleen, lungs and bones in that descending order. After 56 days, there were considerable amounts of Au in the liver, spleen, lungs and bone. The biopersistence studies revealed that Au does not get cleared completely over eight weeks. The bioaccumulation study results showed that Au accumulates in the liver, spleen, lungs and bones albeit in a non-dose dependent fashion. In all the studies reported in this work, there was no peracute and acute toxicity as a result of exposure to AuNPs. In the biopersistence and bioaccumulation studies no peracute, acute, subacute and subchronic toxicity was observed. There were no differences in the levels of markers of liver and kidney damage. No abnormalities were detected during the histopathological analysis of the heart, kidneys, liver, lungs and spleen during the biopersistence and bioaccumulation studies. The acute biodistribution pattern of the Au core was different to that of the citrate surface coating and the Au core distributed widely in the body. The clearance of Au is low after a single intravenous injection over 56 days and Au has a high bioaccumulation propensity which is not dose dependent. Exposure to AuNPs did not result in peracute, acute, subacute and subchronic toxicity in a rodent model.