PEG-coated Gold Nanoparticles Research Articles

Differential interferences with clinical chemistry assays by gold nanorods, and gold and silica nanospheres

Nanomaterials are known to cause interference with several standard toxicological assays. As part of an in vivo study of PEG-coated gold nanorods in mice, nanorods were added to reference serum, and results for standard clinical chemistry parameters were compared with serum analyzed without nanorods. PEG-coated gold nanorods produced several concentration-dependent interferences. Comparisons were then made with PEG-coated gold and silica nanospheres. Interferences were observed for both materials that differed from gold nanorods. Removal of the particles from serum by centrifugation prior to analysis resolved most, but not all of the interferences. Additional clinical chemistry analyzers were used to further investigate trends in assay interference. We conclude that PEG-coated gold and silica nanoparticles can interfere with standard clinical chemistry tests in ways that vary depending upon material, shape, and specific assay methodology employed. Assay interferences by nanomaterials cannot always be predicted, underscoring the need to verify that nanomaterials under study do not interfere with methods used to evaluate potential biological effects.

No overt structural or functional changes associated with PEG-coated gold nanoparticles accumulation with acute exposure in the mouse heart

In this study, we investigated the cardiac biodistribution of polyethylene glycol (PEG)-coated AuNPs and their effects on cardiac function, structure and inflammation in both normal and cardiac remodeling mice. The model of cardiac remodeling was induced by subcutaneously injection of isoproterenol (ISO), a non-selective beta-adrenergic agonist, for 7 days. After AuNPs were injected intravenously in mice for 7 consecutive days, Au content in different organs was determined quantitatively by inductively coupled plasma mass spectrometry (ICP-MS), cardiac function and structure were measured by echocardiography, cardiac fibrosis was examined with picrosirius red staining, the morphology of cardiomyocytes was observed with hematoxylin and eosin (H & E) staining. The accumulation of AuNPs in hearts did not affect cardiac function or induce cardiac hypertrophy, cardiac fibrosis and cardiac inflammation under normal physiological condition. Cardiac AuNPs content was 6-fold higher in the cardiac remodeling mouse than normal mice. However, the increased accumulation of AuNPs in the heart did not aggravate ISO-induced cardiac hypertrophy, cardiac fibrosis or cardiac inflammation. These observations suggest that PEG-coated AuNPs possess excellent biocompatibility under both physiological and pathological conditions. Thus, AuNPs may be safe for cardiac patients and hold great promise for further development for various biomedical applications.

X-ray microscopy and tomography detect the accumulation of bare and PEG-coated gold nanoparticles in normal and tumor mouse tissues

We demonstrate that, with appropriate staining, high-resolution X-ray microscopy can image complicated tissue structures--cerebellum and liver--and resolve large or small amounts of Au nanoparticles in these tissues. Specifically, images of tumor tissue reveal high concentrations of accumulated Au nanoparticles. PEG (poly(ethylene glycol)) coating is quite effective in enhancing this accumulation and significantly modifies the mechanism of uptake by reticuloendothelial system (RES) organs.

Size-dependent radiosensitization of PEG-coated gold nanoparticles for cancer radiation therapy

Gold nanoparticles have been conceived as a radiosensitizer in cancer radiation therapy, but one of the important questions for primary drug screening is what size of gold nanoparticles can optimally enhance radiation effects. Herein, we perform in vitro and in vivo radiosensitization studies of 4.8, 12.1, 27.3, and 46.6 nm PEG-coated gold nanoparticles. In vitro results show that all sizes of the PEG-coated gold nanoparticles can cause a significant decrease in cancer cell survival after gamma radiation. 12.1 and 27.3 nm PEG-coated gold nanoparticles have dispersive distributions in the cells and stronger sensitization effects than 4.8 and 46.6 nm particles by both cell apoptosis and necrosis. Further, in vivo results also show all sizes of the PEG-coated gold nanoparticles can significantly decrease tumor volume and weight after 5 Gy radiations, and 12.1 and 27.3 nm PEG-coated gold nanoparticles have greater sensitization effects than 4.8 and 46.6 nm particles, which can lead to almost complete disappearance of the tumor. In vivo biodistribution confirms that 12.1 and 27.3 nm PEG-coated gold nanoparticles are accumulated in the tumor with high concentrations. The pathology, immune response, and blood biochemistry indicate that the PEG-coated gold nanoparticles have not caused spleen and kidney damages, but give rise to liver damage and gold accumulation. It can be concluded that 12.1 and 27.3 nm PEG-coated gold nanoparticles show high radiosensitivity, and these results have an important indication for possible radiotherapy and drug delivery.

Surface Modification with Alginate-Derived Polymers for Stable, Protein-Repellent, Long-Circulating Gold Nanoparticles

Poly(ethylene) glycol is commonly used to stabilize gold nanoparticles (GNPs). In this study, we evaluated the ability of cysteine-functionalized alginate-derived polymers to both provide colloidal stability to GNPs and avoid recognition and sequestration by the body's defense system. These polymers contain multiple reactive chemical groups (hydroxyl and carboxyl groups) that could allow for ready functionalization with, for example, cell-targeting ligands and therapeutic drugs. We report here that alginate-coupled GNPs demonstrate enhanced stability in comparison with bare citrate-coated GNPs and a similar lack of interaction with proteins in vitro and long in vivo circulation as PEG-coated GNPs.

Size-dependent in vivo toxicity of PEG-coated gold nanoparticles

BackgroundGold nanoparticle toxicity research is currently leading towards the in vivo experiment. Most toxicology data show that the surface chemistry and physical dimensions of gold nanoparticles play an important role in toxicity. Here, we present the in vivo toxicity of 5, 10, 30, and 60 nm PEG-coated gold nanoparticles in mice.MethodsAnimal survival, weight, hematology, morphology, organ index, and biochemistry were characterized at a concentration of 4000 μg/kg over 28 days.ResultsThe PEG-coated gold particles did not cause an obvious decrease in body weight or appreciable toxicity even after their breakdown in vivo. Biodistribution results show that 5 nm and 10 nm particles accumulated in the liver and that 30 nm particles accumulated in the spleen, while the 60 nm particles did not accumulate to an appreciable extent in either organ. Transmission electron microscopic observations showed that the 5, 10, 30, and 60 nm particles located in the blood and bone marrow cells, and that the 5 and 60 nm particles aggregated preferentially in the blood cells. The increase in spleen index and thymus index shows that the immune system can be affected by these small nanoparticles. The 10 nm gold particles induced an increase in white blood cells, while the 5 nm and 30 nm particles induced a decrease in white blood cells and red blood cells. The biochemistry results show that the 10 nm and 60 nm PEG-coated gold nanoparticles caused a significant increase in alanine transaminase and aspartate transaminase levels, indicating slight damage to the liver.ConclusionThe toxicity of PEG-coated gold particles is complex, and it cannot be concluded that the smaller particles have greater toxicity. The toxicity of the 10 nm and 60 nm particles was obviously higher than that of the 5 nm and 30 nm particles. The metabolism of these particles and protection of the liver will be more important issues for medical applications of gold-based nanomaterials in future.

Size-dependent tissue kinetics of PEG-coated gold nanoparticles

Gold nanoparticles (AuNPs) can be used in various biomedical applications, however, very little is known about their size-dependent in vivo kinetics. Here, we performed a kinetic study in mice with different sizes of PEG-coated AuNPs. Small AuNPs (4 or 13 nm) showed high levels in blood for 24 h and were cleared by 7 days, whereas large (100 nm) AuNPs were completely cleared by 24 h. All AuNPs in blood re-increased at 3 months, which correlated with organ levels. Levels of small AuNPs were peaked at 7 days in the liver and spleen and at 1 month in the mesenteric lymph node, and remained high until 6 months, with slow elimination. In contrast, large AuNPs were taken up rapidly (∼ 30 min) into the liver, spleen, and mesenteric lymph nodes with less elimination phase. TEM showed that AuNPs were entrapped in cytoplasmic vesicles and lysosomes of Kupffer cells and macrophages of spleen and mesenteric lymph node. Small AuNPs transiently activated CYP1A1 and 2B, phase I metabolic enzymes, in liver tissues from 24 h to 7 days, which mirrored with elevated gold levels in the liver. Large AuNPs did not affect the metabolic enzymes. Thus, propensity to accumulate in the reticuloendothelial organs and activation of phase I metabolic enzymes, suggest that extensive further studies are needed for practical in vivo applications.

The effect of PEG-coated gold nanoparticles on the anti-proliferative potential of Specific Nutrient Synergy

The role of PEG-coated gold nanoparticles (Au NPs) on the anti-proliferative effect of Specific Nutrient Synergy (SNS) on HTLV-1 infected (C91-PL and HuT-102) and non-infected (CEM and Jurkat) malignant T-lymphocytes cells, was investigated. When PEG-coated Au NPs (of different molecular weights) were added alone, there was no effect on either viability or proliferation of the leukemic cell lines studied. Treatment of cells with SNS and PEG (5 or 10 kDa) coated Au NP reduced significantly the proliferation in all cell lines tested; this reached more than 50% reduction as compared to the control for cells treated for 96 h. Data showed that the best anti-proliferative effect was obtained using SNS and Au NP coated with PEG of molecular weights of 5 and 10 kDa with almost no effect of PEG of lower molecular weights (0.75 and 2 kDa) or higher ones (20 kDa). This was true as well for HTLV-1 infected as for non-infected malignant T-lymphocytes. Electron microscopy results showed uptake of the gold particles to Jurkat cells. All described effects are specific to leukemia cell lines, and no effects were observed with freshly activated human mononuclear lymphocytes as control.

Antibiofouling Polymer Coated Gold@Iron Oxide Nanoparticle (GION) as a Dual Contrast Agent for CT and MRI

In our previous study, we demonstrated the PEG coated gold nano-particles can be used as a novel CT contrast agent for blood pool imaging (angiography) and for diagnosis of hepatoma, suggesting gold nanoparticle-based CT contrast agent may be able to overcome limitations of conventional iodine based contrast agents.

Comparison of gene expression profiles in mice liver following intravenous injection of 4 and 100 nm-sized PEG-coated gold nanoparticles

Gold nanoparticles (AuNPs) have been widely used in various biomedical applications for photothermal therapy, imaging and drug delivery. Although AuNPs have been recognized as a biologically safe material, very little is known about their molecular and cellular effects. To evaluate the gene expression profile and mechanism of the molecular level of polyethylene glycol (PEG)-coated AuNPs and the effect of particle size, we applied an expression profiling approach. PEG-coated AuNPs of different particle sizes, 4 and 100 nm, were intravenously administered to BALB/c mice (4.26 mg/kg, body weight). Thirty minutes after injection of AuNPs, the mice were sacrificed and liver tissues were removed. Then, pathological examination and microarray analysis were performed on the liver tissues. Histology of the liver tissues did not indicate any pathological changes in all treatment groups. Only 0.38% (170 genes) and 0.50% (224 genes) of the total genes (45,000 genes) were significantly induced by the treatment of 4 or 100 nm AuNPs, respectively. In addition, the 4 and 100 nm AuNPs treatment groups shared 67.1% and 50.9% of the significantly changed genes, respectively. Commonly expressed genes by a single intravenous injection of 4 or 100 nm AuNPs were categorized as apoptosis, cell cycle, inflammation, and metabolic process. In the specifically expressed genes of 4 or 100 nm AuNPs, although the genes were different each other, 4 and 100 nm AuNPs showed similar gene categories such as cell cycle, response to stress, signal transduction, and metabolic process. Therefore, we can conclude that 4 and 100 nm AuNPs showed similar biological effects on liver tissues of mice.

Molecular Enhancement of Thermal Ablation Therapies Using TNF-α-Coated Gold Nanoparticles in a Translational Model of Renal Tumors

Thermal ablation therapies are currently used for the treatment of select renal masses. Such treatments are limited to tumors that are small (<3 cm diameter), exophytic, and away from vital structures such as ureter or intestine. Novel treatment approaches are geared towards increasing the size of the thermal lesion created, limiting damage to collateral normal tissues, reducing local recurrence and distant metastases as well as improving the imaging potential of the therapy. Previous studies have demonstrated the enhancement of thermal therapies in pre-clinical murine models of solid tumors by intravenously infusing 33 nm TNF-α and PEG coated gold nanoparticles (CYT-6091, Cytimmune Sciences Inc.) prior to ablation. This study investigates the enhancement of thermal ablation therapy by CYT-6091 in a translational animal model of renal tumors. New Zealand White rabbits (37 for radiofrequency ablation (RFA), 20 for cryoablation) had VX-2 tumors implanted into their bilateral kidneys. The tumors were allowed to grow for 14 days to a size of ∼1 cm. For RFA, the rabbits were split into 3 treatment groups of 10 rabbits each and a sham group of 7 rabbits. The groups were treated with CYT-6091 (200 μg/kg) only, RFA only, or CYT-6091 (200 μg/kg) followed 4 hours later by RFA. For cryoablation, 2 treatment groups of 10 rabbits each were used. The groups were treated with cryoablation only or CYT-6091 (200 μg/kg) followed 4 hours later by cryoablation. The kidneys were harvested 3 days later for RFA and 7 days later for cryoablation. Gross and microscopic measurements of the ablation size as well as histological analysis using H&E staining were performed. The RFA plus CYT-6091 group had a larger zone of complete cell death than the RFA only group when measured both on gross sectioning (0.32±0.03 vs. 0.22±0.07cm3, p=0.015) and on microscopic examination (0.30±0.07 vs. 0.23±0.03cm3, p=0.03). Overall this was a 23% increase in ablation volume. This difference in ablation size was due to a replacement of partially ablated tissue at the periphery in the RFA only group by completely ablated tissue in the RFA plus CYT-6091 group. Thus this zone of partially ablated tissue was smaller in the RFA plus CYT-6091 group than the RFA only group (0.08±0.02cm3 vs. 0.13±0.05cm3, p=0.01). Excessive tumor growth into the ablation lesion at day 7 following cryoablation prevented accurate measurements in these groups; however, a significant decrease in the rate of peritoneal carcinomatosis (metastases) was obtained in the cryo plus CYT-6091 group compared to the cryoablation alone group (1/10 vs. 8/10, p=0.04). We have shown that use of CYT-6091 prior to thermal ablation therapy in a rabbit kidney tumor model can minimize the zone of partial treatment at the periphery of the thermal lesion and thus maximize the complete kill zone in RFA while significantly decreasing the rate of metastases in cryoablation. These data provide preliminary evidence for the efficacy of adjuvant use of CYT-6091 for thermal ablation therapies in a large animal translational tumor model.

Acute toxicity and pharmacokinetics of 13 nm-sized PEG-coated gold nanoparticles

In general, gold nanoparticles are recognized as being as nontoxic. Still, there have been some reports on their toxicity, which has been shown to depend on the physical dimension, surface chemistry, and shape of the nanoparticles. In this study, we carry out an in vivo toxicity study using 13 nm-sized gold nanoparticles coated with PEG (MW 5000). In our findings the 13 nm sized PEG-coated gold nanoparticles were seen to induce acute inflammation and apoptosis in the liver. These nanoparticles were found to accumulate in the liver and spleen for up to 7 days after injection and to have long blood circulation times. In addition, transmission electron microscopy showed that numerous cytoplasmic vesicles and lysosomes of liver Kupffer cells and spleen macrophages contained the PEG-coated gold nanoparticles. These findings of toxicity and kinetics of PEG-coated gold nanoparticles may have important clinical implications regarding the safety issue as PEG-coated gold nanoparticles are widely used in biomedical applications.

Antibiofouling polymer-coated gold nanoparticles as a contrast agent for in vivo x-ray computed tomography imaging

Current computed tomography (CT) contrast agents such as iodine-based compounds have several limitations, including short imaging times due to rapid renal clearance, renal toxicity, and vascular permeation. Here, we describe a new CT contrast agent based on gold nanoparticles (GNPs) that overcomes these limitations. Because gold has a higher atomic number and X-ray absorption coefficient than iodine, we expected that GNPs can be used as CT contrast agents. We prepared uniform GNPs (∼30 nm in diameter) by general reduction of HAuCl4 by boiling with sodium citrate. The resulting GNPs were coated with polyethylene glycol (PEG) to impart antibiofouling properties, which extends their lifetime in the bloodstream. Measurement of the X-ray absorption coefficient in vitro revealed that the attenuation of PEG-coated GNPs is 5.7 times higher than that of the current iodine-based CT contrast agent, Ultravist. Furthermore, when injected intravenously into rats, the PEG-coated GNPs had a much longer blood circulation ...

Antibiofouling Polymer-Coated Gold Nanoparticles as a Contrast Agent for in Vivo X-ray Computed Tomography Imaging

Current computed tomography (CT) contrast agents such as iodine-based compounds have several limitations, including short imaging times due to rapid renal clearance, renal toxicity, and vascular permeation. Here, we describe a new CT contrast agent based on gold nanoparticles (GNPs) that overcomes these limitations. Because gold has a higher atomic number and X-ray absorption coefficient than iodine, we expected that GNPs can be used as CT contrast agents. We prepared uniform GNPs ( approximately 30 nm in diameter) by general reduction of HAuCl4 by boiling with sodium citrate. The resulting GNPs were coated with polyethylene glycol (PEG) to impart antibiofouling properties, which extends their lifetime in the bloodstream. Measurement of the X-ray absorption coefficient in vitro revealed that the attenuation of PEG-coated GNPs is 5.7 times higher than that of the current iodine-based CT contrast agent, Ultravist. Furthermore, when injected intravenously into rats, the PEG-coated GNPs had a much longer blood circulation time (>4 h) than Ultravist (<10 min). Consequently, CT images of rats using PEG-coated GNPs showed a clear delineation of cardiac ventricles and great vessels. On the other hand, relatively high levels of GNPs accumulated in the spleen and liver, which contain phagocytic cells. Intravenous injection of PEG-coated GNPs into hepatoma-bearing rats resulted in a high contrast ( approximately 2-fold) between hepatoma and normal liver tissue on CT images. These results suggest that PEG-coated GNPs can be useful as a CT contrast agent for a blood pool and hepatoma imaging.