Magnetic nanoparticles for theragnostics

Engineered magnetic nanoparticles (MNPs) represent a cutting-edge tool in medicine because they can be simultaneously functionalized and guided by a magnetic field. Use of MNPs has advanced magnetic resonance imaging (MRI), guided drug and gene delivery, magnetic hyperthermia cancer therapy, tissue engineering, cell tracking and bioseparation. Integrative therapeutic and diagnostic (i.e., theragnostic) applications have emerged with MNP use, such as MRI-guided cell replacement therapy or MRI-based imaging of cancer-specific gene delivery. However, mounting evidence suggests that certain properties of nanoparticles (e.g., enhanced reactive area, ability to cross cell and tissue barriers, resistance to biodegradation) amplify their cytotoxic potential relative to molecular or bulk counterparts. Oxidative stress, a 3-tier paradigm of nanotoxicity, manifests in activation of reactive oxygen species (ROS) (tier I), followed by a proinflammatory response (tier II) and DNA damage leading to cellular apoptosis and mutagenesis (tier III). Invivo administered MNPs are quickly challenged by macrophages of the reticuloendothelial system (RES), resulting in not only neutralization of potential MNP toxicity but also reduced circulation time necessary for MNP efficacy. We discuss the role of MNP size, composition and surface chemistry in their intracellular uptake, biodistribution, macrophage recognition and cytotoxicity, and review current studies on MNP toxicity, caveats of nanotoxicity assessments and engineering strategies to optimize MNPs for biomedical use.     

In vitro comparative cytotoxicity study of aminated polystyrene,zinc oxide and silver nanoparticles on a cervical cancer cell line

Nanoparticles use in nano-biotechnology applications have increased significantly with Aminated polystyrene amine (AmPs NP), Zinc oxide (ZnO NP), and Silver (Ag NP) nanoparticles utilized in wide variety of consumer products. This has presented a number of concerns due to their increased exposure risks and associated toxicity on living systems. Changes in the structural and physicochemical properties of nanoparticles can lead to changes in biological activities. This study investigates, compares, and contrasts the potential toxicity of AmPs, ZnO and Ag NPs on an in vitro model (HeLa cells) and assesses the associated mechanism for their corresponding cytotoxicity relative to the surface material. It was noted that NPs exposure attributed to the reduction in cell viability and high-level induction of oxidative stress. All three test particles were noted to induce ROS to varying degrees which is irrespective of the attached surface group. Cell cycle analysis indicated a G2/M phase cell arrest, with the corresponding reduction in G0/G1 and S phase cells resulting in caspase-mediated apoptotic cell death. These findings suggest that all three NPs resulted in the decrease in cell viability, increase intracellular ROS production, induce cell cycle arrest at the G2/M phase and finally result in cell death by caspase-mediated apoptosis, which is irrespective of their differences in physiochemical properties and attached surface groups.     

Gene expression in nanotoxicology research: analysis by differential display in BALB3T3 fibroblasts exposed to cobalt particles and ions

Broadly defined, nanoscale materials are substances in which at least one critical dimension is less than 100 nm. Nanoscale materials are employed in several industrial applications as well as in biology and medicine. Despite their wide use, very little research has been carried out on the potential toxicity of nanoparticles. For this reason, we report on a molecular approach in nanotoxicology research. Using the differential display technique, we focused our attention on mRNA expression in a BALB3T3 A31-1-1 cell line that was not exposed and exposed for 72 h to 1 μM of cobalt microparticles (Co-μ), nanoparticles (Co-nano), and ions. In the experiments, we obtained 10 differentially expressed sequences. These genes represent candidate biomarkers capable of indicating specific cellular effects after Co-nano exposure. In addition, our results show that treatment with Co-nano somehow activates cellular pathways of defense and repair mechanisms. It is also evident that molecular techniques are valuable tools in nanotoxicology research, where they will certainly find wide use.     

Solid lipid nanoparticles reduce systemic toxicity of docetaxel: Performance and mechanism in animal

Abstract

Nanotechnology presents great potential for increasing efficacy of docetaxel while reducing side-effects and toxicity. However, in vivo toxicity of nano-formulation of docetaxel has not been systemically investigated yet. Herein, the new docetaxel-loaded solid lipid nanoparticles (DSNs) were prepared, and systemic toxicity of DSNs in different animals was comprehensively investigated. The experimental results showed that no allergenicity and vascular irritation were induced by DSNs at the highest drug concentration of clinical infusion. The maximum tolerated dose (MTD) of DSNs was as high as 400 mg/kg in mice while the medial lethal dose (LD₅₀) of Taxotere was 149.31 mg/kg. The long-term toxicity of DSNs compared with Taxotere in beagle dogs by intravenous infusion weekly for four weeks showed that the administration of Taxotere at 1 mg/kg brought about severe signs of toxicity such as skin flushing, vocalization and salivation. However, no abnormal reactions appeared on animals treated with DSNs at dose of 4 mg/kg. At the same dose level, DSNs induced more minor decreases in body weight gains, slighter hemotoxicity (changes in some clinical hematology and biochemistry parameters), cardiac toxicity, hepatotoxicity and myelosuppression than Taxotere. These results could provide an important reference for developing the novel delivery system of docetaxel.     

Nanotoxicity of TiO2 nanoparticles to erythrocyte in vitro

Titanium dioxide (TiO(2)) has been considered as non-toxic mineral particles widely used in the fields like cosmetics, food and drug. When the scale come to nanometer, TiO(2) nanoparticles (nano-TiO(2)) exhibits multiple specific characteristics coupled with unknown risks on health. The purpose of this study was to systematically research the influence of nano-TiO(2) on erythrocyte. The results indicated that the erythrocytes treated with nano-TiO(2) underwent abnormal sedimentation, hemagglutination and dose dependent hemolysis, totally differing from those treated with micro-TiO(2). The ghost cells were firstly investigated by using ultra-thin cell section in the case under nano-TiO(2). The mechanism of such adverse effects is (1) the attachment around erythrocyte change the surface native properties and ultimately lead to hemoagglutination; (2) the content leak to the outside of erythrocyte through the breakage induced by both the nano-TiO(2) trans-membrane and the oxidative stress under nano-TiO(2). Our findings imply that nano-TiO(2) may have potential toxicity to human being health.     

Engineered organic nanoparticles to combat biofilms

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Zinc oxide nanoparticles hepatotoxicity: Histological and histochemical study

Zinc oxide nanoparticles (ZnO NPs) are widely used in industry and cosmetic products with promising investment in medical diagnosis and treatment. However, these particles may reveal a high potential risk for human health with no information about hepatotoxicity that might be associated with their exposure. The present work was carried out to investigate the histological and histochemical alterations induced in the hepatic tissues by naked 35 nm ZnO NPs. Male Wistar albino rats were exposed to ZnO NPs at a daily dose of 2 mg/kg for 21 days. Liver biopsies from all rats under study were subjected to histopathological examinations. In comparison with the control rats, the following histological and histochemical alterations were demonstrated in the hepatic tissues of rats exposed to ZnO NPs: sinusoidal dilatation, Kupffer cells hyperplasia, lobular and portal triads inflammatory cells infiltration, necrosis, hydropic degeneration, hepatocytes apoptosis, anisokaryosis, karyolysis, nuclear membrane irregularity, glycogen content depletion and hemosidrosis. The findings of the present work might indicate that ZnO NPs have potential oxidative stress in the hepatic tissues that may affect the function of the liver. More work is needed to elucidate the toxicity and pathogenesis of zinc oxide nanoparticles on the vital organs.     

Cellular distribution and degradation of cobalt ferrite nanoparticles in Balb/3T3 mouse fibroblasts

The effect of the concentration of cobalt ferrite (CoFe₂O₄) nanoparticles (NPs) on their intracellular location and distribution has been explored by synchrotron radiation X-ray and fluorescence microscopy (SR-XRF) monitoring the evolution of NPs elemental composition as well. In cells exposed to low concentrations of CoFe₂O₄ NPs, the NPs preferentially segregate in the perinuclear region preserving their initial chemical content. At concentrations exceeding 500 μM the XRF spectra indicate the presence of Co and Fe also in the nuclear region, accompanied by sensible changes in the cellular morphology. The increase of the Co/Fe ratio measured in the nuclear compartment indicates that above certain concentrations the CoFe₂O₄ NPs intracellular distribution could be accompanied by biodegradation resulting in Co accumulation in the nucleus.     

Effects of nanoparticle size and gestational age on maternal biodistribution and toxicity of gold nanoparticles in pregnant mice

Gold nanoparticles (GNPs) have considerable applications in biomedicine, such as in bio-sensing, bio-imaging, drug delivery and photothermal therapeutics. However, currently there are limited information regarding the impact of pregnancy on their biodistribution, elimination and toxicity. In this study, we investigated the biodistribution and potential toxic effects of different-sized GNPs (1.5, 4.5, 13, 30 and 70 nm in diameter) in non-pregnant and pregnant mice at different gestational ages (E5.5, 7.5, 9.5, 11.5 and 13.5). 5 h after intravenous injection, GNPs exhibited size-dependent biodistribution profiles; however, regardless of size, no significant biodistribution changes were observed between non-pregnant and pregnant mice. Kinetic studies showed that 4.5 nm GNPs were primarily excreted through urine within 5 h, whereas 30 nm GNPs had a more prolonged blood circulation time. No apparent toxic effects (e.g., increased mortality, altered behavior, reduced animal weight, abnormal organ morphology or reduced pregnancy duration) were observed with different-sized GNPs in pregnant mice. However, treatment with 30 nm GNPs induced mild emphysema-like changes in lungs of pregnant mice. These results indicated that the maternal biodistribution patterns of GNPs in pregnant mice depended on particle size, but not gestational age; organ-specific adverse effects may arise with treatment with some GNPs according to their size.     

Intrinsic biological property of colloidal fullerene nanoparticles (nC60): Lack of lethality after high dose exposure to human epidermal and bacterial cells

Colloidal fullerene nanoparticles (nC₆₀) were reported to be toxic to fish brains, human cells and microorganisms, while new observations suggest that the observed toxicity may be due to tetrahydrofuran (THF) solvent or its oxidative by-products in nC₆₀ preparations. Here, we report a novel method for preparing nC₆₀ nanoparticles that does not use THF solvent, but provides nC₆₀ with an average particle size of 43.8 nm and a yield approximately 100 times higher than the THF method. The prepared nC₆₀ showed a similar antioxidant capacity compared to a water-soluble vitamin E analog. No mortality to human epidermal keratinocytes was observed at a concentration 170 times higher than the reported LC₅₀ values for other human cell lines. No toxicity was observed to E. coli or B. subtilis at up to 342 μg/mL nC₆₀ for 16 h, which was hundred times higher than the reported minimum inhibitory concentrations of nC₆₀ prepared using THF method for these two bacteria. When E. coli was exposed to 85.5 μg/mL nC₆₀ with daily passage for 4 days, the stationary phase populations at different passages were not statistically different (p = 0.05) from the control without nC₆₀ nanoparticles. These results reveal that the intrinsic biological property of nC60 is non-toxic, confirming the prior non-toxic reports when using nC₆₀ prepared with non-THF methods.     

银纳米颗粒增强磁流体热疗对脑胶质瘤C6细胞的杀伤作用

目的研究20 nm银纳米颗粒(AgNPs)对脑胶质瘤C6细胞磁流体热疗的作用。方法脑胶质瘤C6细胞分为对照组、AgNPs组、磁流体热疗组和AgNPs结合磁流体热疗组。通过集落形成实验检测20 nm AgNPs对脑胶质瘤C6细胞热疗的效果;流式细胞术检测AgNPs对细胞周期和凋亡率的影响;HE染色检测AgNPs对荷瘤鼠磁流体热疗凋亡的影响。结果与对照组比较,20 nmAgNPs能够引起脑胶质瘤C6细胞G2/M期阻滞,并使细胞在接受磁流体热疗后凋亡率显著提高(P<0.05)。结论银纳米颗粒能提高脑胶质瘤C6细胞的热敏感性。     

The cytotoxicity and genotoxicity of soluble and particulate cobalt in human lung fibroblast cells

Cobalt exposure is increasing as cobalt demand rises worldwide due to its use in enhancing rechargeable battery efficiency, super-alloys, and magnetic products. Cobalt is considered a possible human carcinogen with the lung being a primary target. However, few studies have considered cobalt-induced toxicity in human lung cells. Therefore, in this study, we sought to determine the cytotoxicity and genotoxicity of particulate and soluble cobalt in human lung cells. Cobalt oxide and cobalt chloride were used as representative particulate and soluble cobalt compounds, respectively. Exposure to both particulate and soluble cobalt induced a concentration-dependent increase in cytotoxicity, genotoxicity, and intracellular cobalt ion levels. Based on intracellular cobalt ion levels, we found that soluble cobalt was more cytotoxic than particulate cobalt while particulate and soluble cobalt induced similar levels of genotoxicity. However, soluble cobalt induced cell cycle arrest indicated by the lack of metaphases at much lower intracellular cobalt concentrations compared to cobalt oxide. Accordingly, we investigated the role of particle internalization in cobalt oxide-induced toxicity and found that particle-cell contact was necessary to induce cytotoxicity and genotoxicity after cobalt exposure. These data indicate that cobalt compounds are cytotoxic and genotoxic to human lung fibroblasts, and solubility plays a key role in cobalt-induced lung toxicity.     

The responses of immune cells to iron oxide nanoparticles

Immune cells play an important role in recognizing and removing foreign objects, such as nanoparticles. Among various parameters, surface coatings of nanoparticles are the first contact with biological system, which critically affect nanoparticle interactions. Here, surface coating effects on nanoparticle cellular uptake, toxicity and ability to trigger immune response were evaluated on a human monocyte cell line using iron oxide nanoparticles. The cells were treated with nanoparticles of three types of coatings (negatively charged polyacrylic acid, positively charged polyethylenimine and neutral polyethylene glycol). The cells were treated at various nanoparticle concentrations (5, 10, 20, 30, 50 μg ml^?1 or 2, 4, 8, 12, 20 μg cm^?2) with 6 h incubation or treated at a nanoparticle concentration of 50 μg ml^?1 (20 μg cm^?2) at different incubation times (6, 12, 24, 48 or 72 h). Cell viability over 80% was observed for all nanoparticle treatment experiments, regardless of surface coatings, nanoparticle concentrations and incubation times. The much lower cell viability for cells treated with free ligands (e.g. ~10% for polyethylenimine) suggested that the surface coatings were tightly attached to the nanoparticle surfaces. The immune responses of cells to nanoparticles were evaluated by quantifying the expression of toll‐like receptor 2 and tumor necrosis factor‐α. The expression of tumor necrosis factor‐α and toll‐like receptor 2 were not significant in any case of the surface coatings, nanoparticle concentrations and incubation times. These results provide useful information to select nanoparticle surface coatings for biological and biomedical applications. Copyright © 2016 John Wiley & Sons, Ltd.     

Magnetic iron oxide nanoparticles for drug delivery: applications and characteristics

Introduction: For many years, the controlled delivery of therapeutic compounds has been a matter of great interest in the field of nanomedicine. Among the wide amount of drug nanocarriers, magnetic iron oxide nanoparticles (IONs) stand out from the crowd and constitute robust nanoplatforms since they can achieve high drug loading as well as targeting abilities stemming from their remarkable properties (magnetic and biological properties). These applications require precise design of the nanoparticles regarding several parameters which must be considered together in order to attain highest therapeutic efficacy.

Areas covered: This short review presents recent developments in the field of cancer targeted drug delivery using magnetic nanocarriers as drug delivery systems.

Expert opinion: The design of nanocarriers enabling efficient delivery of therapeutic compounds toward targeted locations is one of the major area of research in the targeted drug delivery field. By precisely shaping the structural properties of the iron oxide nanoparticles, drugs loaded onto the nanoparticles can be efficiently guided and selectively delivered toward targeted locations. With these goals in mind, special attention should be given to the pharmacokinetics and in vivo behavior of the developed nanocarriers.     

氧化铁纳米粒子的制备

目的用共沉淀法制备氧化铁纳米粒子。方法用JEM— 2 0 0 0EXII场发射电子显微镜观察纳米微粒的形貌和粒子大小 ;为了证实磷脂在纳米氧化物表面吸附 ,又进行了红外光谱研究 ;用X -ray分析确定晶体结构和其结晶性质。 结果在磷脂水溶液中 ,用缓慢 -氧化法成功的制备出氧化铁纳米粒子。通过TEM测量粒径为 7nm。纳米氧化物的红外图谱表明 :纳米氧化物的表面已经被磷脂层所覆盖。XRD相分析表明 ,纳米氧化物微粒已经形成     

Iron oxide magnetic nanoparticles as antimicrobials for therapeutics

Abstract

The use of iron oxide magnetic nanoparticles (IMNP) in medical and pharmaceutical areas dates to the beginning of the 1970s, as carriers. Some other uses to these nanoparticles are in vitro separation, magnetic resonance imaging and drug targeting agent. Many preparations containing IMNP have been described and used in drug delivery, hyperthermia, in vitro separation, tissue repair, cellular therapy, for magnetic separation, magnetic resonance imaging, as spoilers for magnetic resonance spectroscopy, and more recently as sensors for metabolites and other biomolecules. The use of these nanostructures as antibacterial agents has also been reported, which could kill some bacteria species causing no damage to the human host cells. Recently, they have been used as hyperthermia agents to treat infections or cancer, which are more susceptible than the healthy host’s cells. Engineering designs, physiochemical characteristics, biomedical applications of IMNP, toxicity and magnetic nanotoxicology have been discussed. However, the application of IMNP as antimicrobials is very important. Thus, this review explores the therapeutic activities of IMNP and their use as antimicrobial agents. These nanoparticles can be efficient for the treatment of microbial infections, probably acting as membrane permeability enhancer, damaging the cell wall or by generating reactive oxygen species.     

2-Amino-2-deoxy-glucose conjugated cobalt ferrite magnetic nanoparticle (2DG-MNP) as a targeting agent for breast cancer cells

In this study, 2-amino-2-deoxy-glucose (2DG) was conjugated to COOH modified cobalt ferrite magnetic nanoparticles (COOH–MNPs), which were designed to target tumor cells as a potential targetable drug/gene delivery agent for cancer treatment. According to our results, it is apparent that, 2DG labeled MNPs were internalized more efficiently than COOH–MNPs under the same conditions in all cell types (MDA-MB-231 and MCF-7 cancer and MCF-10A normal breast cells) (p < 0.001). Moreover, the highest amount of uptake was observed in MDA-MB-231, followed by MCF-7 and normal MCF-10A cells for both MNPs. The apoptotic effects of 2DG-MNPs were further evaluated, and it was found that apoptosis was not induced at low concentrations of 2DG-MNPs in all cell types, whereas dramatic cell death was observed at higher concentrations. In addition, the gene expression levels of four drug-metabolizing enzymes, two Phase I (CYP1A1, CYP1B1) and two Phase II (GSTM3, GSTZ1) were also increased with the high concentrations of 2DG-MNPs.     

Impact of lithiated cobalt oxide and phosphate nanoparticles on rainbow trout gill epithelial cells

Abstract

Metal oxide and phosphate nanoparticles (NPs) are ubiquitous in emerging applications, ranging from energy storage to catalysis. Cobalt-containing NPs are particularly important, where their widespread use raises questions about the relationship between composition, structure, and potential for environmental impacts. To address this gap, we investigated the effects of lithiated metal oxide and phosphate NPs on rainbow trout gill epithelial cells, a model for environmental exposure. Lithium cobalt oxide (LCO) NPs significantly reduced cell viability at10?µg/mL, while a 10-fold higher concentration of lithiated cobalt hydroxyphosphate (LCP) NPs was required to significantly reduce viability. Exposure to Li⁺ and Co²⁺ alone, at concentrations relevant to ion released from the NPs, did not reduce cell viability and minimally impacted reactive oxygen species (ROS) levels. Both LCO- and LCP-NPs were found within membrane-bound organelles. However, only LCP-NPs underwent rapid and complete dissolution in artificial lysosomal fluid. Unlike LCP-NPs, LCO-NPs significantly increased intracellular ROS, could be found within abnormal multilamellar bodies, and induced formation of intracellular vacuoles. Increased p53 gene expression, measured in individual cells, was observed at sub-toxic concentrations of both LCO- and LCP-NPs, implicating both in inductions of cellular damage and stress at concentrations approaching predicted environmental levels. Our results implicate the intact NP, not the dissolved ions, in the observed adverse effects and show that LCO-NPs significantly impact cell viability accompanied by increase in intracellular ROS and formation of organelles indicative of cell stress, while LCP-NPs have minimal adverse effects, possibly due to their rapid dissolution in acidic organelles.     

Genotoxicity of cobalt nanoparticles and ions in Drosophila

Abstract

Nanogenotoxicology is an emergent area of research, relevant for estimating the potential carcinogenic risk of nanomaterials. Since most of the approaches use in vitro studies, and neglecting the whole organism limits the accuracy of the obtained results, we have used Drosophila melanogaster to study the possible genotoxic potential of cobalt nanoparticles (Co NPs). The wing somatic mutation and recombination test has been the test of choice. This test is based on the principle that the loss of heterozygosis and the corresponding expression of the suitable recessive markers, multiple wing hairs and flare-3 can lead to the formation of mutant clone cells in growing up larvae, which are expressed as mutant spots on the wings of adult flies. Co NPs, as well as the ionic form cobalt chloride, were given to third instar larvae through the food, at concentrations ranging from 0.1 to 10 mM. The results obtained indicate that both cobalt forms are able to induce significant increases in the frequency of mutant clones. Although at low concentrations only Co NPs were genotoxic, the level of genetic damage obtained at the highest dose tested of cobalt chloride (10 mM) showed a significant higher increase in the frequency of total spots than those observed after the treatment with cobalt nanoparticles. As conclusion, our results indicate that Co NPs were able to induce genotoxic activity in the wing-spot assay of D. melanogaster, mainly via the induction of somatic recombination. The differences observed in the behaviour of the two selected cobalt forms may result from differences in the uptake.