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.     

Nuclear penetration of surface functionalized gold nanoparticles

Free gold nanoparticles easily aggregate when the environment conditions change. Here, gold nanoparticles (AuNPs) with average diameter of 3.7 nm were prepared and then modified with poly(ethylene glycol) (PEG) to improve stability. The gold nanoparticles were first surface-modified with 3-mercaptopropionic acid (MPA) to form a self-assembled monolayer and subsequently conjugated with NH₂-PEG-NH₂ through amidation between the amine end groups on PEG and the carboxylic acid groups on the particles. The biocompatibility and intracellular fate of PEG-modified gold nanoparticles (AuNP@MPA-PEG) were then studied in human cervical cancer (HeLa) cells. Cell viability test showed that AuNP@MPA-PEG did not induce obvious cytotoxicity. Both confocal laser scanning microscopy and transmission electron microscopy demonstrated that AuNP@MPA-PEG entered into mammalian cells and the cellular uptake of AuNP@MPA-PEG was time-dependent. Inductively coupled plasma mass spectrometry and confocal microscopy imaging further demonstrated that AuNP@MPA-PEG penetrated into the nucleus of mammalian cells upon exposure for 24 h. These results suggest that surface modification can enhance the stability and improve the biocompatibility. This study also indicates that AuNP@MPA-PEG can be used as potential nuclear targeted drug delivery carrier.     

Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages

Spherical and rod-shaped gold nanoparticles with surface poly(ethylene glycol) (PEG) chains were characterized for size, shape, charge, poly dispersity and surface plasmon resonance. The nanoparticles were injected intravenously to 6-8-week-old female nu/nu mice bearing orthotopic ovarian tumors, and their biodistribution in vital organs was compared. Gold nanorods were taken up to a lesser extent by the liver, had longer circulation time in the blood, and higher accumulation in the tumors, compared with their spherical counterparts. The cellular uptake of PEGylated gold nanoparticles by a murine macrophage-like cell line as a function of geometry was examined. Compared to nanospheres, PEGylated gold nanorods were taken up to a lesser extent by macrophages. These studies point to the importance of gold nanoparticle geometry and surface properties on transport across biological barriers.     

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.     

Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration

Gold nanoparticles (GNP) provide many opportunities in imaging, diagnostics, and therapies of nanomedicine. Hence, their biokinetics in the body are prerequisites for specific tailoring of nanomedicinal applications and for a comprehensive risk assessment.We administered ¹⁹⁸Au-radio-labelled monodisperse, negatively charged GNP of five different sizes (1.4, 5, 18, 80, and 200 nm) and 2.8 nm GNP with opposite surface charges by intravenous injection into rats. After 24 h, the biodistribution of the GNP was quantitatively measured by gamma-spectrometry.The size and surface charge of GNP strongly determine the biodistribution. Most GNP accumulated in the liver increased from 50% of 1.4 nm GNP to >99% of 200 nm GNP. In contrast, there was little size-dependent accumulation of 18-200 nm GNP in most other organs. However, for GNP between 1.4 nm and 5 nm, the accumulation increased sharply with decreasing size; i.e. a linear increase with the volumetric specific surface area. The differently charged 2.8 nm GNP led to significantly different accumulations in several organs.We conclude that the alterations of accumulation in the various organs and tissues, depending on GNP size and surface charge, are mediated by dynamic protein binding and exchange. A better understanding of these mechanisms will improve drug delivery and dose estimates used in risk assessment.     

Unraveling the cell-type dependent radiosensitizing effects of gold through the development of a multifunctional gold nanoparticle

The radiosensitizing efficacy of gold is well established, however, there remain several significant barriers to the successful clinical translation of nano-sized gold particles (AuNPs). These barriers include: retaining stability in relevant biological sera, demonstrating effectiveness at clinically relevant AuNP concentrations and identifying the biological context where significant benefit is most likely to be achieved. Herein we have developed a AuNP preparation, stress-tested to provide effective protection from salt and serum mediated agglomeration. Furthermore, the core AuNP is co-functionalized with two biologically derived peptides designed to enhance endocytosis and promote endosomal escape, thus maximizing intracellular AuNP surface area. In summary, these investigations demonstrate restored AuNP internalization using the co-functionalized preparation that generated significant radiosensitization, in both in vitro and in vivo models, at clinically viable treatment concentrations. Furthermore, we have identified an underpinning biological mechanism in the inherent radical scavenging capacity that could be used to predict radiosensitizing efficacy.     

Functionalized gold nanoparticles for sensing of pesticides: A review

Pesticides are a family of non-biodegradable chemical compounds which widely used in agriculture to control pests and increase yield production. However, overuse or abuse of pesticides and their metabolites may cause potential toxicity for the environment as well as human health and all other living organisms, even at deficient concentrations. Consequently, the development of sensors for monitoring these compounds is significant. Recently, nanoparticles-based sensors have been extensively employed as a potential alternative or complementary analytical tool to conventional detection methods for pesticides. Among them, gold nanoparticles (AuNPs) owing to their unique optical properties have been developed as smart sensors with high selectivity, sensitivity, simplicity, and portability. These comprehensive reviews have summarized various studies performed based on different detection strategies, i.e., colorimetric, fluorescence, surface-enhanced Raman scattering, and electrochemical, using AuNPs as sensing probes for pesticide analysis in various matrices. Additionally, the current challenges and future trends for developing novel AuNPs-based sensors for the detection of pesticides are also discussed.     

Modeling gold nanoparticle biodistribution after arterial infusion into perfused tissue: effects of surface coating,size and protein corona

Abstract

A detailed understanding of the factors governing nanomaterial biodistribution is needed to rationally design safe nanomedicines. This research details the pharmacokinetics of gold nanoparticle (AuNP) biodistribution after arterial infusion of 40 or 80?nm AuNP (1?μg/ml) into the isolated perfused porcine skin flap (IPPSF). AuNP had surface coatings consisting of neutral polyethylene glycol (PEG), anionic lipoic acid (LA), or cationic branched polyethylenimine (BPEI). Effect of a porcine plasma corona (PPC) on 40?nm BPEI and PEG-AuNP were assessed in the IPPSF. Au concentrations were determined by ICP/MS and arterial to venous concentration-time profiles were analyzed over 8?hr (4?hr infusion, 4?hr washout) using a two-compartment pharmacokinetic model. IPPSF viability and vascular function were assessed by change in glucose utilization, vascular resistance, or weight gain after perfusion. All AuNP demonstrated some degree of AuNP arterial extraction and skin flap retention, as well as enhanced kinetic parameters of tissue uptake; with BPEI-AuNP consistently having the greatest biodistribution even with a PPC. Toxicological effects were not detected. Transmission electron microscopy confirmed intracellular uptake of AuNP. These studies paralleled previous in vitro cell culture studies using the same AuNP in human endothelial and renal proximal tubule cells, hepatocytes, keratinocytes, showing BPEI-AuNP having the greatest uptake, although the presence of a PPC did not reduce IPPSF biodistribution as in the cell culture studies. These findings clearly indicate arterial to the venous extraction of AuNP after infusion with the magnitude of extraction being greatest with the BPEI surface coating and provide data and model structure necessary to construct the whole body physiologically based pharmacokinetic models capable of utilizing available in vitro data.     

Surface functionalities of gold nanoparticles impact embryonic gene expression responses

Abstract

Incorporation of gold nanoparticles (AuNPs) into consumer products is increasing; however, there is a gap in available toxicological data to determine the safety of AuNPs. In this study, we utilised the embryonic zebrafish to investigate how surface functionalisation and charge influence molecular responses. Precisely engineered AuNPs with 1.5 nm cores were synthesised and functionalized with three ligands: 2-mercaptoethanesulfonic acid (MES), N,N,N-trimethylammoniumethanethiol (TMAT), or 2-(2-(2-mercaptoethoxy)ethoxy)ethanol. Developmental assessments revealed differential biological responses when embryos were exposed to the functionalised AuNPs at the same concentration. Using inductively coupled plasma–mass spectrometry, AuNP uptake was confirmed in exposed embryos. Following exposure to MES- and TMAT-AuNPs from 6 to 24 or 6 to 48 h post fertilisation, pathways involved in inflammation and immune response were perturbed. Additionally, transport mechanisms were misregulated after exposure to TMAT and MES-AuNPs, demonstrating that surface functionalisation influences many molecular pathways.     

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.     

Exploring gold nanoparticles interaction with mucins: A spectroscopic-based study

The interaction between two mucin types (mucin from porcine stomach – PGM and mucin from bovine submaxillary glands – BSM) and gold nanoparticles (GNPs) of various size (5, 20 and 40?nm) and functionalization (with cysteamine or thioglycolic acid) was studied under physiological conditions, in order to investigate the affinity of the nanoparticles to the proteins.Different methods are employed to monitor the interactions: UV–vis and fluorescence spectroscopy, fluorescence lifetime, circular dichroism and transmission electron microscopy. These studies have shown the formation of a complex between GNPs and both PGM and BSM.This aspect could be of great importance for the use of gold nanoparticles for biomedical purposes in those diseases where qualitative and quantitative mucin anomalies play an essential role in mucus composition and rheology.     

The interaction of sonochemically synthesized gold nanoparticles with serum albumins

Spherical gold nanoparticles of approximately 16 nm were synthesized using a sonochemical reduction method and characterized using UV–vis spectroscopy, atomic force microscopy (AFM) and transmission electron microscopy (TEM). The binding of these gold nanoparticles with bovine serum albumin (BSA) and human serum albumin (HSA) was investigated using UV–vis absorption and fluorescence spectroscopic techniques. A strong quenching of the fluorescence from serum albumins was observed due to the formation of a ground state complex with gold nanoparticles (static quenching). The fluorescence quenching constants, number of binding sites and binding constants were determined using Stern–Volmer and Benesi–Hildebrand plots. Using Forster Resonance Energy Transfer (FRET) theory, the distance between the donor (serum albumins) and acceptor (gold nanoparticles) was obtained, which showed that HSA has more affinity towards sonochemically synthesized gold nanoparticles compared to gold nanoparticles synthesized using other methods.     

Antibacterial activity of biosynthesized gold nanoparticles using biomolecules from Lignosus rhinocerotis and chitosan

A simple, cost-effective, and environmentally friendly method is needed for synthesizing metal nanoparticles, including gold nanoparticles (AuNPs). In this study, AuNPs were synthesized with Lignosus rhinocerotis sclerotial extract (LRE) and chitosan (CS) as reducing and stabilizing agents, respectively. Different LRE concentrations from cold and hot water extraction (CWE and HWE, respectively) were used to reduce chloroauric acid (HAuCl₄) to form AuNPs. Positively charged chitosan stabilized AuNPs (CS-AuNPs) mediated by LRE exhibited a surface plasmon resonance (SPR) band at 533?nm. The CS-AuNPs synthesized using CWE had a smaller particle size (49.5?±?6.7–82.4?±?28.0?nm) compared to that of the HWE samples (80.3?±?23.4–125.3?±?41.5?nm), depending on LRE concentration. FTIR results suggested protein and polysaccharides in LRE were the sources of reducing power, reducing gold ions to AuNPs. CS-AuNPs were mostly spherical with higher LRE concentrations, whereas some triangular, pentagonal, irregular, and rod shaped AuNPs were observed at lower LRE concentrations. CS-AuNPs mediated by LRE displayed effective antibacterial activity against gram-negative (Pseudomonas aeruginosa and Escherichia coli) and gram-positive bacteria (Staphylococcus aureus and Bacillus sp.). Thus, the biosynthesized AuNPs using LRE and chitosan provide opportunities for developing stable and eco-friendly nanoparticles with effective antibacterial properties.     

载巯基化阿霉素的中空金纳米粒的制备与光热性能研究

目的 制备一种载阿霉素（DOX）的中空金纳米粒（HGNPs）载体。方法 合成巯基化阿霉素（DOX-SH）,通过质谱（MS ESI）和核磁共振氢谱（1H-NMR）对其结构进行表征,再将其以金硫键共价结合方式负载到中空金纳米粒表面。通过粒径、等离子共振吸收（SPR）、透射电子显微镜（TEM）、近红外（NIR）激发的光热转化实验和细胞毒性实验对制备的中空金纳米粒载药体系进行评价。结果 质谱显示,合成的巯基化阿霉素的分子量为616,核磁共振氢谱所示的结构也与目标产物相符。阿霉素-中空金纳米粒复合载药体系(HGNPs-DOX)的粒径为70 nm左右;等离子共振吸收最大吸收波长为800 nm左右,具有良好的光热转化能力;透射电子显微镜显示,其为中空圆球形结构,壳厚4~6 nm;细胞毒性显示,在高浓度时,阿霉素-中空金纳米粒复合载药体系能显著减小阿霉素的毒性。结论 成功合成了阿霉素-中空金纳米粒复合载体,其具有良好的结构,良好的光热转化能力,较小的细胞毒性,未来可成为有研究前景的新一代化疗联合光热治疗的递送载体。     

Synthesis and in vitro studies of gold nanoparticles loaded with docetaxel

The aim of these studies was to synthesize, characterize and evaluate the efficacy of pegylated gold nanoparticles (AuNPs) that differed in their PEG molecular weight, using PEG 550 and PEG 2000. The synthesis of the gold nanoparticles was carried out by modified Brust method with a diameter of 4–15 nm. The targeting agent folic acid was introduced by the covalent linkage. Finally, the anti-cancer drug docetaxel was encapsulated by the AuNPs by non covalent adsorption. The nanoparticles were characterized by transmission electron microscopy and used for in vitro studies against a hormone-responsive prostate cancer cell line, LnCaP. The loaded nanoparticles reduced the cell viability in more than 50% at concentrations of 6 nM and above after 144 h of treatment. Moreover, observation of prostate cancer cells by optical microscopy showed damage to the cells after exposure to drug-loaded AuNPs while unloaded AuNPs had much less effect.     

Influence of PEG coating on the oral bioavailability of gold nanoparticles in rats

Metallic nanoparticles can be produced in a variety of shapes, sizes, and surface chemistries, making them promising potential tools for drug delivery. Most studies to date have evaluated uptake of metallic nanoparticles from the GI tract with methods that are at best semi-quantitative. This study used the classical method of comparing blood concentration area under the curve (AUC) following intravenous and oral doses to determine the oral bioavailability of 1, 2 and 5?kDa PEG-coated 5?nm gold nanoparticles (AuNPs). Male rats were given a single intravenous dose (0.8?mg/kg) or oral (gavage) dose (8?mg/kg) of a PEG-coated AuNP, and the concentration of gold was measured in blood over time and in tissues (liver, spleen and kidney) at sacrifice. Blood concentrations following oral administration were inversely related to PEG size, and the AUC in blood was significantly greater for the 1?kDa PEG-coated AuNPs than particles coated with 2 or 5?kDa PEG. However, bioavailabilities of all of the particles were very low (相似文献   

Vascular tube formation and angiogenesis induced by polyvinylpyrrolidone-coated silver nanoparticles

Silver nanoparticles (AgNPs) are one of the most commonly used nanomaterials due to their antibacterial properties. In this study, we examined the effects of polyvinylpyrrolidone (PVP)-coated AgNPs (average size 2.3 nm) on angiogenesis in both an in vivo model and an in vitro endothelial cell line, SVEC4-10. Increased angiogenesis was detected around the injection site of AgNP-containing Matrigel in vivo. AgNPs also increased the infiltration of endothelial cells and the hemoglobin (Hb) content in AgNP-Matrigel plugs implanted into mice. AgNPs induced endothelial cell tube formation on growth factor-reduced Matrigel, production of reactive oxygen species (ROS), and production of angiogenic factors, such as vascular endothelial growth factor (VEGF) and nitric oxide (NO), in SVEC4-10 cells. In addition, AgNPs promoted the activation of FAK, Akt, ERK1/2, and p38, which are all involved in VEGF receptor (VEGFR)-mediated signaling. Finally, AgNP-treated tumors caused angiogenesis around tumors in B16F10 melanomas after they were injected into mice, and the Hb concentration in the tumors increased in a concentration-dependent manner with AgNP treatment. Thus, our study suggests that exposure to AgNPs can cause angiogenesis through the production of angiogenic factors.