J. Swanner, I. Tenvooren, B.W. Bernish, C.D. Fahrenholtz, P.A. Vidi, R. Singh
Wake Forest School of Medicine,
Keywords: oxidative stress, therapy, redox, nanoparticle, silver, intravenous, systemic delivery, mouse
Summary:Triple negative breast cancers (TNBC) are characterized by loss of expression of hormone receptors and low expression of the human epidermal growth factor receptor 2 (HER2). TNBC patients do not benefit from current anti-HER2 or hormone-positive targeted breast cancer treatments. Molecular profiling of breast cancer has found that TNBC is largely comprised of basal-like and claudin-low intrinsic molecular subtypes. Claudin-low breast cancer (CLBC) accounts for approximately one third of TNBCs, but many CLBC tumors may also be non-TNBC. Because different types of breast cancer respond differently to treatments, there is no “one-size fits all” therapy. For the development of novel breast cancer therapeutics, attention must be paid to therapeutic efficacy in specific sub-types of the disease. We discovered a type of silver nanoparticle (AgNP) that is selectively cytotoxic for treatment of CLBC at doses that are non-toxic to non-cancerous breast and ineffective for treatment of other breast cancer molecular subtypes. We show that this property is not shared by ionic silver and is therefore one of the first examples of a “new to nano” cytotoxic property. Mechanistically, we find that AgNPs induce DNA damage, oxidative damage to protein thiols, unfolded protein stress responses (UPR), and apoptotic cell death in CLBC cells without causing similar damage or cell death in non-cancerous breast cells, both in traditional monolayer and 3D cell culture grown on basement membrane. Furthermore, we find that AgNPs traffic to different subcellular locations in CLBC as compared to non-cancerous breast cells. We establish that the CLBC-selective cytotoxic properties of AgNPs are independent of particle size and use tumor spheroids to develop AgNPs that readily diffuse through extracellular matrix. Most significantly, we conducted a 3 month in vivo safety/efficacy study in CLBC tumor-bearing mice and show that optimally designed AgNPs can be delivered repeatedly at substantial doses by the intravenous route and are effective for treatment of tumors without systemic toxicity. This is the first time any nanomaterial has been demonstrated to possess a breast cancer subtype-specific cytoxicity profile. Significantly, our research provides evidence that a therapeutic window exists for the safe in vivo use of AgNPs, and therefore offers a possibility of a major benefit to the poor prognosis, CLBC patient population.