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.
Highlights
Triple‐negative breast cancer (TNBC) is an aggressive, malignant neoplasia characterized by lack or decreased expression of estrogen, progesterone, and human epidermal growth factor receptors
We show for the first time that systemically administered silver nanoparticle (AgNP) are effective for reducing the growth of solid, TNBC
Preclinical cancer models represent an important tool for the development of new cancer therapies, and use of multiple cell culture and mouse models of human cancer is the most likely method to predict the efficacy of novel anti‐cancer treatments.[45]
Summary
Triple‐negative breast cancer (TNBC) is an aggressive, malignant neoplasia characterized by lack or decreased expression of estrogen, progesterone, and human epidermal growth factor receptors. A recent case report describes the complete regression of metastatic head and neck cancer in a patient who ingested AgNPs, in the absence of other anticancer therapy, after failure of platinum‐ and taxane‐based chemotherapy, radiation, and surgical resection.[31] These studies support the potential for wider clinical use of AgNPs for cancer therapy, AgNPs are pleotropic stressors, and it is necessary to consider sub‐lethal, off‐target toxicity which could affect their safety and potential for clinical translation.[32,33]. We evaluate the hypothesis that an exploitable vulnerability to AgNPs exists in TNBC cells, and we determine how size, shape, or coating affects the sensitivity of TNBC cells to AgNPs. To determine potential off‐target, sub‐lethal effects of AgNPs, we quantify the impact of AgNPs on ER stress, DNA damage, cell polarity, and apoptosis in non‐cancerous breast epithelial cells using monolayer and 3D tumor organoid cultures in vitro. These studies help to link cell culture to murine and eventual human studies, and will guide future advancements in the use of AgNPs for treatment of TNBC
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