Silver Nanoparticles Inhibit Metastasis of 4T1 Tumor in Mice after Intragastric but Not Intravenous Administration

The potential anticancer activity of different silver nanoformulations is increasingly recognized. In the present work, we use the model of 4T1 tumor in BALB/ccmdb immunocompetent mice to analyze the impact of citrate- and PEG-coated silver nanoparticles (AgNPs) on the development and metastatic potential of breast cancer. One group of mice was intragastrically administered with 1 mg/kg body weight (b.w.) of AgNPs daily from day 1 to day 14 after cancer cells implantation (total dose 14 mg/kg b.w.). The second group was intravenously administered twice with 1 or 5 mg/kg b.w. of AgNPs. A tendency for lowering tumor volume on day 21 (mean volumes 491.31, 428.88, and 386.83 mm³ for control, AgNPs-PEG, and AgNPs-citrate, respectively) and day 26 (mean volumes 903.20, 764.27, and 672.62 mm³ for control, AgNPs-PEG, and AgNPs-citrate, respectively) has been observed in mice treated intragastrically, but the effect did not reach the level of statistical significance. Interestingly, in mice treated intragastrically with citrate-coated AgNPs, the number of lung metastases was significantly lower, as compared to control mice (the mean number of metastases 18.89, 14.90, and 8.03 for control, AgNPs-PEG, and AgNPs-citrate, respectively). No effect of AgNPs treatment on the number of lung metastases was observed after intravenous administration (the mean number of metastases 12.44, 9.86, 12.88, 11.05, and 10.5 for control, AgNPs-PEG 1 mg/kg, AgNPs-PEG 5 mg/kg, AgNPs-citrate 1 mg/kg, and AgNPs-citrate 5 mg/kg, respectively). Surprisingly, inhibition of metastasis was not accompanied by changes in the expression of genes associated with epithelial-mesenchymal transition. Instead, changes in the expression of inflammation-related genes were observed. The presented results support the antitumor activity of AgNPs in vivo, but the effect was limited to the inhibition of metastasis. Moreover, our results clearly point to the importance of AgNPs coating and route of administration for its anticancer activity. Finally, our study supports the previous findings that antitumor AgNPs activity may depend on the activation of the immune system and not on the direct action of AgNPs on cancer cells.