Genotoxicity evaluation of stearic acid grafted chitosan oligosaccharide nanomicelles

Abstract

Stearic acid grafted chitosan oligosaccharide (CSO-SA) nanomicelles could be promptly internalized into cancer cells; therefore, it is regarded as a promising drug carrier for cancer therapy. However, the toxicity of CSO-SA is not clear. In the present study, the genotoxic effects of CSO-SA nanomicelles (with high substitution degree of SA, 42.6±3.8%) were evaluated with a battery of genotoxicity assays. Mutagenicity was not found in Ames Salmonella/microsome mutagenicity assay (Ames test), while mild but definite positive results were observed in mouse bone marrow micronucleus assay and single cell gel electrophoresis (SCGE or comet assay) in A549 cells. CSO-SA was also found to induce apoptosis and oxidative stress through the induction of reactive oxygen species (ROS) in a dose-dependent manner in A549 cells. Preincubation with the free radical scavenger N-acetyl-l-cysteine (NAC) decreased the intracellular ROS level and alleviated the DNA damage in A549 cells. Expression levels of cleaved poly ADP-ribose polymerase (PARP), caspase-9 and caspase-3, markers of apoptosis, were significantly higher in CSO-SA treated cells. In conclusion, these results suggested significant genotoxicity of high doses of CSO-SA nanomicelles in vivo and in vitro. Oxidative stress was, at least partially, the possible mechanism underlying the genotoxicity induced by CSO-SA.