Adsorption of proteins on oral Zn2+ doped iron oxide nanoparticles in mouse stomach and in vitro: triggering nanoparticle aggregation.

Oral route is one of the most important portals of nanoparticle entry to the body. However, in vivo protein corona formed in the gastrointestinal tract has not been studied owing to the difficulty for the recovery of nanoparticles from the in vivo environment. In this study, by using the magnetic property of iron oxide nanoparticles (Fe3O4 NPs) and Zn2+ doped iron oxide nanoparticles (Zn0.4Fe2.6O4 NPs), the nanoparticles were separated from the gastric fluid after oral administration in mice. The effects of Zn2+ doping and static magnetic field (SMF) treatment on the protein adsorption on the nanoparticles were investigated in vitro and in vivo. Zn2+ doping decreases the adsorption of pepsin on the nanoparticles in vitro and affects the composition of the protein corona in vivo and enhances protein adsorption-induced aggregation of the nanoparticles in vitro and in vivo. SMF treatment affects the composition of the protein corona of Fe3O4 NPs and Zn0.4Fe2.6O4 NPs, and enhances the aggregation of Fe3O4 NPs and Zn0.4Fe2.6O4 NPs in vivo. Furthermore, the results demonstrate that electrostatic attraction is the crucial force to drive adsorption of proteins on Fe3O4 NPs and Zn0.4Fe2.6O4 NPs and protein adsorption-induced change in the surface charge of nanoparticles plays an important role in the pH-dependent aggregation of the nanoparticles. In addition, the work provides the evidence that the protein adsorption-induced aggregation of Fe3O4 NPs and Zn0.4Fe2.6O4 NPs has no effect on their magnetic susceptibility. The results highlight that Zn0.4Fe2.6O4 NPs may be used as a potential oral magnetic resonance imaging contrast agent in diagnosis of gastrointestinal disease.

Evidence of Translocation of Oral Zn2+ Doped Magnetite Nanoparticles Across the Small Intestinal Wall of Mice and Deposition in Spleen: Unique Advantage in Biomedical Applications.

Nanomaterials have been widely applied in oral drug delivery. A number of indirect evidences suggest that nanoparticles can pass across gastrointestinal walls to enter the blood circulation system. However, there is still no direct evidence to prove that the intact nanoparticles can pass across gastrointestinal walls and the nanoparticles can retain their original structure after translocation across gastrointestinal walls. In the present study, the potential toxicity of dimercaptosuccinic acid coated Zn2+ doped magnetite nanoparticles (DMSA-Zn0.4Fe2.6O4) in the spleen, stomach, and small intestine of mice has been investigated after 30 days of repeated intragastric administration. We provide first direct evidence that intact DMSA-Zn0.4Fe2.6O4 can pass across the small intestinal barriers to enter blood circulation system and arrive in the spleen. In addition, our findings provide direct evidence that although the biotransformation of DMSA-Zn0.4Fe2.6O4 occurs in vivo, some DMSA-Zn0.4Fe2.6O4 retain their original structure after translocation across the small intestinal wall and deposition in the spleen. The results indicate the safety of DMSA-Zn0.4Fe2.6O4 in the applications in mice at a 50 mg/kg dose and highlight the unique advantage of DMSA-Zn0.4Fe2.6O4 in biomedical applications.

INOS-mediated acute stomach injury and recovery in mice after oral exposure to halloysite nanotubes.

Natural halloysite nanotubes (HNTs) with a hollow lumen are already applied in numerous fields and enter the environment in increasing quantities, which may have effects on animal and human health. However their in vivo toxicity in mammals is still largely unclear. The aim of this study is to assess acute oral toxicity of HNTs in the stomach of mice and recovery. Oral HNTs at low dose (5 mg HNTs/kg BW) for 30 days increased in daily food and water intake and promoted mouse growth with no obvious adverse effect on the stomach. The promotive effect on mouse growth disappeared after cessation of oral administration of the nanotubes. Oral HNTs for 30 days at high dose (50 mg HNTs/kg BW) induced Si and Al accumulation in the stomach, which caused oxidative stress, inflammation and iNOS-mediated damage in the organ. The damage in the stomach led to slight atrophic gastritis and reduced mouse growth. Oral HNTs-induced changes at high dose were not observed after a 30-days recovery period. The findings provided the evidence that oral HNTs-induced acute toxicity in the stomach was reversible. More importantly, this research showed that Al and Si were cleared out of the mice by hepatic excretion and renal excretion, respectively, during the recovery period. The results suggest that HNTs at low concentration in environments have no adverse effect on mice, while there are health risks to mice under severe contamination by HNTs.

Halloysite Nanotubes-Induced Al Accumulation and Fibrotic Response in Lung of Mice after 30-Day Repeated Oral Administration.

Natural halloysite (Al2Si2O5(OH)4· nH2O) nanotubes (HNT) are clay materials with hollow tubular structure and are widely applied in many fields. Many in vitro studies indicate that HNTs exhibit a high level of biocompatibility; however, the in vivo toxicity of HNTs remains unclear. In this study, the biodistribution and pulmonary toxicity of the purified HNTs in mice were investigated after intragastric administration for 30 days. HNTs have high stability in biological conditions. Oral administration of HNTs caused significant Al accumulation predominantly in the lung with relative slight effects on Si biodistribution. Oral administration of HNTs stimulated the growth of the mice at low dose (5 mg/kg BW) with no pulmonary toxicity but inhibited the mouse growth and resulted in oxidative stress and inflammation in lung at high dose (50 mg/kg BW). In addition, oral HNTs at high dose could be absorbed from the gastrointestinal tract and deposited in lung and could also induce pulmonary fibrosis.

Halloysite nanotubes-induced Al accumulation and oxidative damage in liver of mice after 30-day repeated oral administration.

Halloysite (Al2 Si2 O5 (OH)4 ·nH2 O) nanotubes (HNTs) are natural clay materials and widely applied in many fields due to their natural hollow tubular structures. Many in vitro studies indicate that HNTs exhibit a high level of biocompatibility, however the in vivo toxicity of HNTs remains unclear. The objective of this study was to assess the hepatic toxicity of the purified HNTs in mice via oral route. The purified HNTs were orally administered to mice at 5, 50, and 300 mg/kg body weight (BW) every day for 30 days. Oral administration of HNTs stimulated the growth of the mice at the low dose (5 mg/kg BW) with no liver toxicity, but inhibited the growth of the mice at the middle (50 mg/kg BW) and high (300 mg/kg BW) doses. In addition, oral administration of HNTs at the high dose caused Al accumulation in the liver but had no marked effect on the Si content in the organ. The Al accumulation caused significant oxidative stress in the liver, which induced hepatic dysfunction and histopathologic changes. These findings demonstrated that Al accumulation-induced oxidative stress played an important role in the oral HNTs-caused liver injury.