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Plasmonic imaging of human oral cancer cell communities during programmed cell death by nuclear-targeting silver nanoparticles.

ABSTRACT: Plasmonic nanoparticles (NPs) have become a useful platform in medicine for potential uses in disease diagnosis and treatment. Recently, it has been reported that plasmonic NPs conjugated to nuclear-targeting peptides cause DNA damage and apoptotic populations in cancer cells. In the present work, we utilized the plasmonic scattering property and the ability of nuclear-targeted silver nanoparticles (NLS/RGD-AgNPs) to induce programmed cell death in order to image in real-time the behavior of human oral squamous carcinoma (HSC-3) cell communities during and after the induction of apoptosis. Plasmonic live-cell imaging revealed that HSC-3 cells behave as nonprofessional phagocytes. The induction of apoptosis in some cells led to attraction of and their subsequent engulfment by neighboring cells. Attraction to apoptotic cells resulted in clustering of the cellular community. Live-cell imaging also revealed that, as the initial concentration of NLS/RGD-AgNPs increases, the rate of self-killing increases and the degree of attraction and clustering decreases. These results are discussed in terms of the proposed mechanism of cells undergoing programmed cell death.

SUBMITTER: Austin LA

PROVIDER: S-EPMC4721227 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Plasmonic imaging of human oral cancer cell communities during programmed cell death by nuclear-targeting silver nanoparticles.

Austin Lauren A LA Kang Bin B Yen Chun-Wan CW El-Sayed Mostafa A MA

Journal of the American Chemical Society 20111018 44

Plasmonic nanoparticles (NPs) have become a useful platform in medicine for potential uses in disease diagnosis and treatment. Recently, it has been reported that plasmonic NPs conjugated to nuclear-targeting peptides cause DNA damage and apoptotic populations in cancer cells. In the present work, we utilized the plasmonic scattering property and the ability of nuclear-targeted silver nanoparticles (NLS/RGD-AgNPs) to induce programmed cell death in order to image in real-time the behavior of hum ...[more]

PMID: 21981727

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Project description:A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients.Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-?) and interleukin-2 (IL-2) production were quantitated by flow cytometry.Lymphocytes from septic patients produced decreased IFN-? and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-?, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-? and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01).In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.

Project description:BackgroundPrecisely how silver nanoparticles (AgNPs) kill mammalian cells still is not fully understood. It is not clear if AgNP-induced damage differs from silver cation (Ag+), nor is it known how AgNP damage is transmitted from cell membranes, including endosomes, to other organelles. Cells can differ in relative sensitivity to AgNPs or Ag+, which adds another layer of complexity to identifying specific mechanisms of action. Therefore, we determined if there were specific effects of AgNPs that differed from Ag+ in cells with high or low sensitivity to either toxicant.MethodsCells were exposed to intact AgNPs, Ag+, or defined mixtures of AgNPs with Ag+, and viability was assessed. The level of dissolved Ag+ in AgNP suspensions was determined using inductively coupled plasma mass spectrometry. Changes in reactive oxygen species following AgNP or Ag+ exposure were quantified, and treatment with catalase, an enzyme that catalyzes the decomposition of H2O2 to water and oxygen, was used to determine selectively the contribution of H2O2 to AgNP and Ag+ induced cell death. Lipid peroxides, formation of 4-hydroxynonenol protein adducts, protein thiol oxidation, protein aggregation, and activation of the integrated stress response after AgNP or Ag+ exposure were quantified. Lastly, cell membrane integrity and indications of apoptosis or necrosis in AgNP and Ag+ treated cells were examined by flow cytometry.ResultsWe identified AgNPs with negligible Ag+ contamination. We found that SUM159 cells, which are a triple-negative breast cancer cell line, were more sensitive to AgNP exposure less sensitive to Ag+ compared to iMECs, an immortalized, breast epithelial cell line. This indicates that high sensitivity to AgNPs was not predictive of similar sensitivity to Ag+. Exposure to AgNPs increased protein thiol oxidation, misfolded proteins, and activation of the integrated stress response in AgNP sensitive SUM159 cells but not in iMEC cells. In contrast, Ag+ cause similar damage in Ag+ sensitive iMEC cells but not in SUM159 cells. Both Ag+ and AgNP exposure increased H2O2 levels; however, treatment with catalase rescued cells from Ag+ cytotoxicity but not from AgNPs. Instead, our data support a mechanism by which damage from AgNP exposure propagates through cells by generation of lipid peroxides, subsequent lipid peroxide mediated oxidation of proteins, and via generation of 4-hydroxynonenal (4-HNE) protein adducts.ConclusionsThere are distinct differences in the responses of cells to AgNPs and Ag+. Specifically, AgNPs drive cell death through lipid peroxidation leading to proteotoxicity and necrotic cell death, whereas Ag+ increases H2O2, which drives oxidative stress and apoptotic cell death. This work identifies a previously unknown mechanism by which AgNPs kill mammalian cells that is not dependent upon the contribution of Ag+ released in extracellular media. Understanding precisely which factors drive the toxicity of AgNPs is essential for biomedical applications such as cancer therapy, and of importance to identifying consequences of unintended exposures.

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Plasmonic imaging of human oral cancer cell communities during programmed cell death by nuclear-targeting silver nanoparticles.

Publications

Plasmonic imaging of human oral cancer cell communities during programmed cell death by nuclear-targeting silver nanoparticles.

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