Assessment of Systemic Toxicity, Genotoxicity, and Early Phase Hepatocarcinogenicity of Iron (III)-Tannic Acid Nanoparticles in Rats.

Iron-tannic acid nanoparticles (Fe-TA NPs) presented MRI contrast enhancement in both liver cancer cells and preneoplastic rat livers, while also exhibiting an anti-proliferative effect via enhanced autophagic death of liver cancer cells. Hence, a toxicity assessment of Fe-TA NPs was carried out in the present study. Acute and systemic toxicity of intraperitoneal Fe-TA NPs administration was investigated via a single dose of 55 mg/kg body weight (bw). Doses were then repeated 10 times within a range of 0.22 to 5.5 mg/kg bw every 3 days in rats. Furthermore, clastogenicity was assessed by rat liver micronucleus assay. Carcinogenicity was evaluated by medium-term carcinogenicity assay using glutathione S-transferase placental form positive foci as a preneoplastic marker, while three doses ranging from 0.55 to 17.5 mg/kg bw were administered 10 times weekly via intraperitoneum. Our study found that the LD50 value of Fe-TA NPs was greater than 55 mg/kg bw. Repeated dose administration of Fe-TA NPs over a period of 28 days and 10 weeks revealed no obvious signs of systemic toxicity, clastogenicity, and hepatocarcinogenicity. Furthermore, Fe-TA NPs did not alter liver function or serum iron status, however, increased liver iron content at certain dose in rats. Notably, antioxidant response was observed when a dose of 17.5 mg/kg bw was given to rats. Accordingly, our study found no signs of toxicity, genotoxicity, and early phase hepatocarcinogenicity of Fe-TA NPs in rats.

MRI contrast enhancement of liver pre-neoplasia using iron-tannic nanoparticles.

The most challenging part of liver cancer detection is finding it in the very early stages. It has been argued that liver preneoplasia is found at the very earliest stages of liver cancer. The presence of a lesion is closely related to the development of HCC. We report herein a new class of iron-based T1 MRI contrast agents which are nanoparticles of iron-tannic complexes (so-called Fe-TA NPs) that can be used for detecting liver preneoplasia. Preliminary assessment of their toxicity in healthy rats provides suitable imaging dose ranges with acceptable toxicity. In diethylnitrosamine (DEN) induced rats, it is shown that Fe-TA NPs are capable of enhancing MRI signals in rat livers having pre-neoplastic lesions within 60 minutes post-injection. The enhancement efficacy is strongly dependent on the characteristics of pre-neoplastic foci (GST-P+ foci). The highest enhancement was in good correlation with the size of GST-P+ foci and amount of Fe-TA NPs accumulated in the liver, and might be caused by the dysfunction of liver sinusoids along with cellular uptake capability of pre-neoplastic hepatocytes. Our results show that Fe-TA NPs are of great interest to develop as an efficient MRI imaging agent for risk assessment of liver cancer.