Abstract
The thermoplasmonic properties of platinum nanoparticles (PtNPs) render them desirable for use in diagnosis, detection, therapy, and surgery. However, their toxicological effects and impact at the molecular level remain obscure. Nanotoxicology is mainly focused on the interactions of nanostructures with biological systems, particularly with an emphasis on elucidating the relationship between the physical and chemical properties such as size and shape. Therefore, we hypothesized whether these unique anisotropic nanoparticles could induce cytotoxicity similar to that of spherical nanoparticles and the mechanism involved. Thus, we synthesized unique and distinct anisotropic PtNPs using lycopene as a biological template and investigated their biological activities in model human acute monocytic leukemia (THP-1) macrophages. Exposure to PtNPs for 24 h dose-dependently decreased cell viability and proliferation. Levels of the cytotoxic markers lactate dehydrogenase and intracellular protease significantly and dose-dependently increased with PtNP concentration. Furthermore, cells incubated with PtNPs dose-dependently produced oxidative stress markers including reactive oxygen species (ROS), malondialdehyde, nitric oxide, and carbonylated protein. An imbalance in pro-oxidants and antioxidants was confirmed by significant decreases in reduced glutathione, thioredoxin, superoxide dismutase, and catalase levels against oxidative stress. The cell death mechanism was confirmed by mitochondrial dysfunction and decreased ATP levels, mitochondrial copy numbers, and PGC-1α expression. To further substantiate the mechanism of cell death mediated by endoplasmic reticulum stress (ERS), we determined the expression of the inositol-requiring enzyme (IRE1), (PKR-like ER kinase) PERK, activating transcription factor 6 (ATF6), and activating transcription factor 4 ATF4, the apoptotic markers p53, Bax, and caspase 3, and the anti-apoptotic marker Bcl-2. PtNPs could activate ERS and apoptosis mediated by mitochondria. A proinflammatory response to PtNPs was confirmed by significant upregulation of interleukin-1-beta (IL-1β), interferon γ (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin (IL-6). Transcriptomic and molecular pathway analyses of THP-1 cells incubated with the half maximal inhibitory concentration (IC50) of PtNPs revealed the altered expression of genes involved in protein misfolding, mitochondrial function, protein synthesis, inflammatory responses, and transcription regulation. We applied transcriptomic analyses to investigate anisotropic PtNP-induced toxicity for further mechanistic studies. Isotropic nanoparticles are specifically used to inhibit non-specific cellular uptake, leading to enhanced in vivo bio-distribution and increased targeting capabilities due to the higher radius of curvature. These characteristics of anisotropic nanoparticles could enable the technology as an attractive platform for nanomedicine in biomedical applications.
Highlights
Over the past decade, both academia and industry became interested in the development of novel nanoparticles (NPs) to detect and/or treat cancer and other infectious diseases [1,2], and efforts were directed toward the development of unique nano-sized materials
We investigated the biological consequences of these 441 differentially expressed genes (DEGs) using gene ontology (GO) analyses and found that genes associated immune responses, various antiviral responses, responses to unfolded proteins, transfer RNA aminoacylation, l-serine biosynthesis, responses to mechanical stimulus, positive regulation of angiogenesis, and cellular response to hormone stimulus were changed (Figure 12B)
We investigated the effects of these platinum NPs (PtNPs) on THP-1 cells to determine their potential applications to consumer products
Summary
Both academia and industry became interested in the development of novel nanoparticles (NPs) to detect and/or treat cancer and other infectious diseases [1,2], and efforts were directed toward the development of unique nano-sized materials. Due to their enhanced surface area-to-volume ratio, NPs have unique physicochemical properties and characteristic features compared with their bulk counterparts, such as augmented catalytic potential, distinctive plasmonic signatures, and enhanced transport capabilities that could be suitable for medical and industrial applications. Ultra-small PtNPs induce cellular stress, cytotoxicity, DNA damage, and genotoxicity in vivo and in vitro in human monocytic [22], U2OS [18], and prostate cancer (LNCaP) cell lines [17]
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