The toxicity and distribution of iron oxide–zinc oxide core‐shell nanoparticles in C57BL/6 mice after repeated subcutaneous administration

Abstract

Therapeutic cancer vaccines promote immune responses by delivering tumour-specific antigens. Recently, we developed iron oxide (Fe3 O4 )-zinc oxide (ZnO) core-shell nanoparticles (CSNPs) as carriers for antigen delivery into dendritic cells (DCs), and the CSNPs were injected subcutaneously into C57BL/6 mice to examine the systemic toxicity, tissue distribution and excretion of the CSNPs. The doses injected were 0, 4, 20 and 200 mg kg(-1) weekly for 4 weeks. No significant changes were observed after the CSNPs administration with respect to mortality, clinical observations, body weight, food intake, water consumption, urinalysis, haematology, serum biochemistry,and organ weights. A dose-dependent increase in granulomatous inflammation was observed at the injection site of the CSNP-treated animals, but no other histopathological lesions in other organs could be attributed to the CSNPs. The Zn concentration, which is an indicator for CSNPs, was not significantly higher in the sampled tissues, urine, or faeces after the CSNP injection. In contrast, the Zn concentration at the subcutaneous skin of the site injected with the CSNPs increased in a dose-dependent manner, along with a macroscopic deposition of the CSNPs. The CSNP residue at the injection site resulted in a foreign body response with the appearance of macrophage infiltration, but otherwise did not show any systemic distribution or toxicity at up to 200 mg kg(-1) during this study. In conclusion, CSNPs could be used as good antigen carriers for DC-based immunotherapy, although further study is needed to completely clear the residue of the CSNPs at the injection site.

Environmental implications and applications of engineered nanoscale magnetite and its hybrid nanocomposites: A review of recent literature

“…Administration of Fe3O4-ZnO core-shell NPs does not cause significant changes to mice with respect to mortality, clinical observations, body weight, food intake, water consumption, urinalysis, haematology, serum biochemistry, and organ weights [112]. A 52-day continuous semi-static waterborne exposure (test media renewed daily) regimen was employed to investigate the accumulation and elimination profiles of two iron oxide NMs (nano-Fe2O3 and nano-Fe3O4) in zebrafish (Danio rerio).…”

Biocompatibility evaluation of pH and glutathione-responsive nanohydrogels after intravenous administration

“…When comparing AST, ALT and ALP blood serum levels, the results obtained from all treatment groups were in the reference value range, 57.49-95.55 U/L, 21.66-51.66 U/L and 31.79-60.81 U/L, respectively [35], which could be interpreted as the absence of hepatocellular damage after the intravenous injection of nanohydrogel. In addition, as a kidney function marker, BUN was also in the normal value range in all of the treatment groups [47], while CRE blood concentration was higher in NMBA-crosslinked NG treated groups. However, these creatinine values were in accordance with reference normal values (0.23-0.92 mg/dL) which might be interpreted as the absence of severe renal toxicity after the injection of these nanohydrogels [35,36].…”

Generation of protective immunity against Orientia tsutsugamushi infection by immunization with a zinc oxide nanoparticle combined with ScaA antigen

“…Administration of excess ZNPs, ranging up to hundreds of mg/kg, via those routes can induce transient toxicity and inflammation in the affected organs, potentially due to dissolution of ZNPs and generation of ROS, but the excess ZNPs are not retained and are eventually eliminated from the system [38, 44]. In a few studies on the systemic toxicity of ZNPs or ZnO-containing NPs after parenteral administration [16, 45], transient accumulation of NPs, as well as local inflammation, in several internal organs or injection site have been observed. However, administered NPs were gradually removed from the body and the animals did not develop any significant systemic inflammation nor any detectable morbidity [16, 45].…”

“…Our recent study in which mice were subcutaneously injected with iron oxide (Fe 3 O 4 )–zinc oxide (ZnO) core–shell nanoparticles also resulted in foreign body responses in the form of macrophage infiltration, but otherwise did not show any systemic distribution or toxicity at up to 200 mg kg −1 [16]. Nevertheless, ZNPs exposure might induce strong local inflammation at the injection site [17] and this can be linked to the generation of antigen-specific adaptive immune responses, including antibodies as well as T cell responses, when combined with a specific protein antigen [18].…”