Fe-N Co-Doped Titanium Dioxide Nanoparticles Induce Cell Death in Human Lung Fibroblasts in a p53-Independent Manner

The advancement of nanotechnology in the last decade has developed an abundance of novel and intriguing TiO2-based nanomaterials that are widely used in many sectors, including industry (as a food additive and colorant in cosmetics, paints, plastics, and toothpaste) and biomedicine (photoelectrochemical biosensing, implant coatings, drug delivery, and new emerging antimicrobial agents). Therefore, the increased use of engineered nanomaterials in the industry has raised serious concern about human exposure and their unexpected cytotoxic effects. Since inhalation is considered the most relevant way of absorbing nanomaterials, different cell death mechanisms induced in MRC-5 lung fibroblasts, following the exposure to functionalized TiO2 NPs, were investigated. Long-term exposure to TiO2 nanoparticles co-doped with 1% of iron and nitrogen led to the alteration of p53 protein activity and the gene expression controlled by this suppressor (NF-kB and mdm2), DNA damage, cell cycle disruptions at the G2/M and S phases, and lysosomal membrane permeabilization and the subsequent release of cathepsin B, triggering the intrinsic pathway of apoptosis in a Bax- and p53-independent manner. Our results are of major significance, contributing to the understanding of the mechanisms underlying the interaction of these nanoparticles with in vitro biological systems, and also providing useful information for the development of new photocatalytic nanoparticles that are active in the visible spectrum, but with increased biocompatibility.