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Project description:Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 Receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent induced significant antitumor effects suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases support a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anti-cancer immune (nano)adjuvant properties to generate therapeutic benefit without requiring uptake by cancer cells. HuHER2 transgenic mice that developed palpable primary mammary tumors were assigned randomly into one of two groups (n = 3/group) to receive either PBS or BP (5 mg Fe/mouse). Mice were sacrificed 7 days after treatment and tumors, lungs, livers, spleens, lymph nodes, and bone marrows were collected. All nanoparticle-containing organs collected from BP treated mice were divided into two equal sections except for lungs (no detectable nanoparticle accumulation). One section was processed for RNA isolation from whole organ. The other tissue/organ section was further processed for magnetic sorting. These were digested to provide single cells as described before28,38 and nanoparticle associated cells were separated magnetically to obtain the nanoparticle-associated fraction (BP-NA). RNA was isolated from BP-NA cells from each organ and tumor and used for sequencing. For Nanostring analysis, HuHER2 transgenic tumor bearing mice were treated with PBS or BP (5 mg Fe) on the day of tumor detection (n = 12/group). Three mice from each group were sacrificed on day 1, 3, 7, or 31 and primary tumors collected for RNA isolation and gene expression analysis by Nanostring using the pan-immune cell marker panel.
2024-03-22 | GSE261779 | GEO
Project description:Systemic exposure to starch-coated iron oxide nanoparticles (IONPs) can stimulate antitumor T cell responses, even when little IONP is retained within the tumor. Here, we demonstrate in mouse models of metastatic breast cancer that IONPs can alter the host immune landscape leading to systemic immune-mediated disease suppression. We report that a single intravenous injection of IONPs can inhibit primary tumor growth, suppress metastases, and extend survival. Gene expression analysis revealed activation of Toll-like receptor (TLR) pathways involving signaling via Toll/Interleukin-1 Receptor domain-containing adaptor-inducing IFN-β (TRIF), a TLR pathway adaptor protein. Requisite participation of TRIF in suppressing tumor progression was demonstrated with histopathologic evidence of upregulated IFN-regulatory factor 3 (IRF3), a downstream protein, and confirmed in a TRIF knockout syngeneic mouse model of metastatic breast cancer. Neither starch-coated polystyrene nanoparticles lacking iron, nor iron-containing dextran-coated parenteral iron replacement agent induced significant antitumor effects suggesting a dependence on the type of IONP formulation. Analysis of multiple independent clinical databases support a hypothesis that upregulation of TLR3 and IRF3 correlates with increased overall survival among breast cancer patients. Taken together, these data support a compelling rationale to re-examine IONP formulations as harboring anti-cancer immune (nano)adjuvant properties to generate therapeutic benefit without requiring uptake by cancer cells.
2024-03-22 | GSE261778 | GEO
Project description:Actein (AT) is a triterpene glycoside isolated from the rhizomes of Cimicifuga foetida that has been investigated for its antitumor effects. AT treatment leads to apoptosis in various cell types, including breast cancer cells, by regulating different signaling pathways. Iron oxide (Fe3O4) magnetic nanoparticles (MNPs) are nanomaterials with biocompatible activity and low toxicity. In the present study, the possible benefits of AT in combination with MNPs on non-small-cell lung cancer (NSCLC) were explored in in vitro and in vivo studies. AT-MNP treatment contributed to apoptosis in NSCLC cells, as evidenced by activation of the caspase 3-signaling pathway, which was accompanied by downregulation of the antiapoptotic proteins Bcl2 and BclXL, and upregulation of the proapoptotic signals Bax and Bad. The death receptors of TRAIL were also elevated following AT-MNP treatment in a p53-dependent manner. Furthermore, a mouse xenograft model in vivo revealed that AT-MNP treatment exhibited no toxicity and suppressed NSCLC growth compared to either AT or MNP monotherapies. In conclusion, this study suggests a novel therapy to induce apoptosis in suppressing NSCLC growth in a p53-dependent manner by combining AT with Fe3O4 MNPs.
| S-EPMC5655152 | biostudies-literature
Project description:The combined treatment with nanoparticles and autophagy inhibitors, such as chloroquine (CQ) and hydroxychloroquine (HCQ), is extensively explored for cancer therapy. However, the toxicity of autophagy inhibitors and their unselective for tumoricidal autophagy have seriously hindered the application of the combined treatment. In this study, a carboxy-functional iron oxide nanoparticle (Fe2O3@DMSA) is designed and identified to significantly exert an antitumor effect without adding CQ or HCQ. Further investigation indicates that the effective inhibition effect of Fe2O3@DMSA alone on hepatoma growth is triggered by inhibiting the fusion of autophagosomes and lysosomes to enhance tumoricidal autophagy, which is induced by intracellular iron-retention-induced sustained reactive oxygen species (ROS) production. Furthermore, in two hepatoma-bearing mouse models, Fe2O3@DMSA alone effectively suppresses the growth of tumors without obvious toxic side effects. These studies offer a promising strategy for cancer therapy.
| S-EPMC7435245 | biostudies-literature
Project description:BackgroundMagnetic drug targeting (MDT) is an effective alternative for common drug applications, which reduces the systemic drug load and maximizes the effect of, eg, chemotherapeutics at the site of interest. After the conjugation of a magnetic carrier to a chemotherapeutic agent, the intra-arterial injection into a tumor-afferent artery in the presence of an external magnetic field ensures the accumulation of the drug within the tumor tissue.Materials and methodsIn this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) coated with lauric acid and human serum albumin as carriers for paclitaxel (SPIONLA-HSA-Ptx). To investigate whether this particle system is suitable for a potential treatment of cancer, we investigated its physicochemical properties by dynamic light scattering, ζ potential measurements, isoelectric point titration, infrared spectroscopy, drug release quantification, and magnetic susceptibility measurements. The cytotoxic effects were evaluated using extensive toxicological methods using flow cytometry, IncuCyte® live-cell imaging, and growth experiments on different human breast cancer cell lines in two- and three-dimensional cell cultures.ConclusionThe data showed that next to their high magnetization capability, SPIONLA-HSA-Ptx have similar cytostatic effects on human breast cancer cells as pure paclitaxel, suggesting their usage for future MDT-based cancer therapy.
| S-EPMC6306067 | biostudies-literature
Project description:Until now, the Food and Drug Administration (FDA)-approved iron supplement ferumoxytol and other iron oxide nanoparticles have been used for treating iron deficiency, as contrast agents for magnetic resonance imaging and as drug carriers. Here, we show an intrinsic therapeutic effect of ferumoxytol on the growth of early mammary cancers, and lung cancer metastases in liver and lungs. In vitro, adenocarcinoma cells co-incubated with ferumoxytol and macrophages showed increased caspase-3 activity. Macrophages exposed to ferumoxytol displayed increased mRNA associated with pro-inflammatory Th1-type responses. In vivo, ferumoxytol significantly inhibited growth of subcutaneous adenocarcinomas in mice. In addition, intravenous ferumoxytol treatment before intravenous tumour cell challenge prevented development of liver metastasis. Fluorescence-activated cell sorting (FACS) and histopathology studies showed that the observed tumour growth inhibition was accompanied by increased presence of pro-inflammatory M1 macrophages in the tumour tissues. Our results suggest that ferumoxytol could be applied 'off label' to protect the liver from metastatic seeds and potentiate macrophage-modulating cancer immunotherapies.
| S-EPMC5198777 | biostudies-literature
Project description:Given the increased use of iron-containing nanoparticles in a number of applications, it is important to understand any effects that iron-containing nanoparticles can have on the environment and human health. Since iron concentrations are extremely low in body fluids, there is potential that iron-containing nanoparticles may influence the ability of bacteria to scavenge iron for growth, affect virulence and inhibit antimicrobial peptide (AMP) function. In this study, Pseudomonas aeruginosa (PA01) and AMPs were exposed to iron oxide nanoparticles, hematite (?-Fe2O3), of different sizes ranging from 2 to 540 nm (2 ± 1, 43 ± 6, 85 ± 25 and 540 ± 90 nm) in diameter. Here we show that the greatest effect on bacterial growth, biofilm formation, and AMP function impairment is found when exposed to the smallest particles. These results are attributed in large part to enhanced dissolution observed for the smallest particles and an increase in the amount of bioavailable iron. Furthermore, AMP function can be additionally impaired by adsorption onto nanoparticle surfaces. In particular, lysozyme readily adsorbs onto the nanoparticle surface which can lead to loss of peptide activity. Thus, this current study shows that co-exposure of nanoparticles and known pathogens can impact host innate immunity. Therefore, it is important that future studies be designed to further understand these types of impacts.
| S-EPMC4158920 | biostudies-literature
Project description:It is challenging to visualize noninvasively the formation of neutrophil extracellular traps, known as NETosis, and therefore difficult to monitor disease progression. A desirable molecular imaging probe is the iron oxide nanoparticle (NP) that could induce reactive oxygen species. Here, we used C57BL/6 mice with pristane-induced lupus, which mimics systemic lupus erythematosus. Administration of anti-Ly6G antibody-conjugated NP allowed detection of NETosis with fluorescent molecular imaging, as evidenced by flow cytometric analysis of citrullinated histone H3 expression in lung neutrophils. This finding was consistent with NP-induced blood NETosis in a spontaneous lupus model of B6.MRL-lpr mice. A chronic assessment was performed in which the lupus mice were protected from enhanced oxidative burst by anti-Ly6G NP. This NP can migrate from the peritoneal cavity to the lungs, as visualized by magnetic particle imaging. Overall, our study provides evidence for a highly sensitive assessment of NETosis in lupus through magnetic particle imaging.
| S-EPMC9382280 | biostudies-literature
Project description:Increasing evidence shows that lungs can be damaged by inhalation of nanoparticles (NPs) at environmental and occupational settings. Recent findings have associated the exposure to iron oxide (Fe2O3) and titanium dioxide (TiO2) - NPs widely used in biomedical and clinical research - with pulmonary oxidative stress and inflammation. Although changes on cellular mechanics could contribute to pulmonary inflammation, there is no information regarding the effects of Fe2O3 and TiO2 on alveolar epithelial cell biomechanics. The aim was to investigate the NPs-induced biomechanical effects in terms of cell stiffness and traction forces exerted by human alveolar epithelial cells. Cell Young's modulus (E) measured by atomic force microscopy in alveolar epithelial cells significantly decreased after exposure to Fe2O3 and TiO2 (?28 and ?25%, respectively) compared to control conditions. Moreover, both NPs induced a similar reduction in the traction forces exerted by the alveolar epithelial cells in comparison to the control conditions. Accordingly, immunofluorescence images revealed a reduction of actomyosin stress fibers in response to the exposure to NPs. However, no inflammatory response was detected. In conclusion, an acute exposure of epithelial pulmonary cells to Fe2O3 and TiO2 NPs, which was mild since it was non-cytotoxic and did not induce inflammation, modified cell biomechanical properties which could be translated into damage of the epithelial barrier integrity, suggesting that mild environmental inhalation of Fe2O3 and TiO2 NPs could not be innocuous.
| S-EPMC6707084 | biostudies-literature
Project description:Iron oxide nanoparticles (IONPs) are chemically inert materials and have been mainly used for imaging applications and drug deliveries. However, the possibility whether they can be used as therapeutic drugs themselves has not yet been explored. We reported here that Fe2O3 nanoparticles (NPs) can protect hearts from ischemic damage at the animal, tissue and cell level. The cardioprotective activity of Fe2O3 NPs requires the integrity of nanoparticles and is not dependent upon their surface charges and molecules that were integrated into nanoparticles. Also, Fe2O3 NPs showed no significant toxicity towards normal cardiomyocytes, indicative of their potential to treat cardiovascular diseases.
| S-EPMC4341209 | biostudies-literature