Silver nanoparticles selectively treat triple‐negative breast cancer cells without affecting non‐malignant breast epithelial cells in vitro and in vivo

Abstract

Silver nanoparticles (AgNPs) show promise for treatment of aggressive cancers including triple‐negative breast cancer (TNBC) in preclinical cancer models. For clinical development of AgNP‐based therapeutics, it will be necessary to clearly define the specific physicochemical features of the nanoparticles that will be used, and to tie these properties to biological outcomes. To fill this knowledge gap, we performed thorough structure/function, mechanistic, safety, and efficacy studies to assess the potential for AgNPs to treat TNBC. We establish that AgNPs, regardless of size, shape, or stabilizing agent, are highly cytotoxic to TNBC cells at doses that are not cytotoxic to non‐malignant breast epithelial cells. In contrast, TNBC cells and non‐malignant breast epithelial cells are similarly sensitive to exposure to silver cation (Ag+), indicating that the nanoparticle formulation is essential for the TNBC‐specific cytotoxicity. Mechanistically, AgNPs are internalized by both TNBC and non‐malignant breast cells, but are rapidly degraded only in TNBC cells. Exposure to AgNPs depletes cellular antioxidants and causes endoplasmic reticulum stress in TNBC cells without causing similar damage in non‐malignant breast epithelial cells. AgNPs also cause extensive DNA damage in 3D TNBC tumor nodules in vitro, but do not disrupt the normal architecture of breast acini in 3D cell culture, nor cause DNA damage or induce apoptosis in these structures. Lastly, we show that systemically administered AgNPs are effective at non‐toxic doses for reducing the growth of TNBC tumor xenografts in mice. This work provides a rationale for development of AgNPs as a safe and specific TNBC treatment.

Silver Nanoparticles Induce Mitochondrial Protein Oxidation in Lung Cells Impacting Cell Cycle and Proliferation

“…Previous studies indicated that the size and coating of AgNPs could affect the toxicity profile of AgNPs in colorectal cancer and murine monocyte/macrophage cell lines [40]. In contrast, we previously observed that size, shape, and coating of AgNPs did not affect the toxicity profile of AgNPs in triple negative breast cancer cell lines [41]. Thus, the toxicity of AgNPs is determined by both the physical and chemical properties of AgNPs and by the metabolic phenotype of cells.…”

Silver nanoparticles: Synthesis, medical applications and biosafety

“…Tumor cells exhibit intact cell structure under light microscope, such as round nuclei, intact nuclear membrane, homogeneous chromatin, normal mitochondria and rough endoplasmic reticulum 40 . The ultrastructural changes of AgNPs-exposed tumor cells are in a dose- and time-dependent manner 246 . Generally, the higher the concentration of AgNPs and the longer the exposure time, the more serious the damage of cell ultrastructure.…”

Green Chemistry Synthesis of Silver Nanoparticles and Their Potential Anticancer Effects

“…AgNPs have been investigated intensively regarding their promising anticancer effects exhibited in different human cancer cell lines, such as endothelial cells, IMR-90 lung fibroblasts, U251 glioblastoma cells and MDA-MB-231 breast cancer cells [40,106,155,156]. AgNPs showed great promises as effective anti-tumor drug-delivery systems [157].…”