Biodistribution and acute toxicity of naked gold nanoparticles in a rabbit hepatic tumor model

Abstract

There is a paucity of data regarding the safety of administering solid gold nanoparticles (AuNPs) in large animal tumor models. We assessed the acute toxicity and biodistribution of 5 nm and 25 nm solid AuNPs in New Zealand White rabbits (n = 6 in each) with implanted liver Vx2 tumors 24 h after intravenous injection. Gold concentration was determined by inductively coupled plasma atomic emission spectrometry (ICP) and imaged with transmission electron microscopy (TEM). There was no clinico-pathologic evidence of renal, hepatic, pulmonary, or other organ dysfunction. After 25 nm AuNP administration, the concentration of white blood cells increased after treatment (p = 0.001). Most other blood studies were unchanged. AuNPs were distributed to the spleen, liver, and Vx2 tumors, but not to other tissues. The urinary excretion of AuNPs was bimodal as measured by ICP. 25 nm AuNPs were more evenly distributed throughout tissues and may be better tools for medical therapy.     

Mechanism of anti-angiogenic property of gold nanoparticles: role of nanoparticle size and surface charge

Discovering therapeutic inorganic nanoparticles (NPs) is evolving as an important area of research in the emerging field of nanomedicine. Recently, we reported the anti-angiogenic property of gold nanoparticles (GNPs): It inhibits the function of pro-angiogenic heparin-binding growth factors (HB-GFs), such as vascular endothelial growth factor 165 (VEGF165) and basic fibroblast growth factor (bFGF), etc. However, the mechanism through which GNPs imparts such an effect remains to be investigated. Using GNPs of different sizes and surface charges, we demonstrate here that a naked GNP surface is required and core size plays an important role to inhibit the function of HB-GFs and subsequent intracellular signaling events. We also demonstrate that the inhibitory effect of GNPs is due to the change in HB-GFs conformation/configuration (denaturation) by the NPs, whereas the conformations of non-HB-GFs remain unaffected. We believe that this significant study will help structure-based design of therapeutic NPs to inhibit the functions of disease-causing proteins.

From the Clinical Editor

In this landmark paper by Arvizo and colleagues, the angiogenesis inhibitor effects of gold nanoparticles were investigated as the function of size and charge. This study will pave the way to the development of therapeutic NPs that inhibit the functions of pathogenic proteins.     

Tumor associated macrophages and angiogenesis dual-recognizable nanoparticles for enhanced cancer chemotherapy

Tumor-associated macrophages (TAMs) and angiogenesis are increasingly considered as the pivotal factors that affect tumor progress. Herein, we developed the paclitaxel (PTX)-loaded nanoparticles (NP/PTX) and decorated it with an innovative peptide YI (YINP/PTX) for simultaneously targeting delivery of drug to TAMs and angiogenesis. We demonstrated that the modification of YI peptide significantly enhanced the internalization of nanoparticles by cells and accumulation of nanoparticles in tumor tissues, but down regulated the distribution of them in normal tissues especially the liver. We also made a confirmation that the YI peptide decorated nanoparticles had an excellent co-localization with TAMs and angiogenesis in vivo. Finally, in the HT-26 colorectal tumor-bearing mice, a pharmacodynamic evaluation was performed and results showed that the YINP/PTX was more effective than other PTX formulations in anti-tumor growth. These results together suggested that the prepared nanoparticles are promising in targeting delivery of chemotherapeutics to tumor microenvironment for enhancing tumor therapy effect.     

Synthesis and antimicrobial effects of silver nanoparticles produced by chemical reduction method

BACKGROUND AND THE PURPOSE OF THE STUDY: The most prominent nanoparticles for medical uses are nanosilver particles which are famous for their high anti-microbial activity. Silver ion has been known as a metal ion that exhibit anti-mold, anti-microbial and anti-algal properties for a long time. In particular, it is widely used as silver nitrate aqueous solution which has disinfecting and sterilizing actions. The purpose of this study was to evaluate the antimicrobial activity as well as physical properties of the silver nanoparticles prepared by chemical reduction method. METHODS: Silver nanoparticles (NPs) were prepared by reduction of silver nitrate in the presence of a reducing agent and also poly [N-vinylpyrolidone] (PVP) as a stabilizer. Two kinds of NPs were synthesized by ethylene glycol (EG) and glucose as reducing agent. The nanostructure and particle size of silver NPs were confirmed by scanning electron microscopy (SEM) and laser particle analyzer (LPA). The formations of the silver NPs were monitored using ultraviolet- visible spectroscopy. The anti-bacterial activity of silver NPs were assessed by determination of their minimum inhibitory concentrations (MIC) against the Gram positive (Staphylococcus aureus and Staphylococcus epidermidis) as well as Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria. RESULTS AND CONCLUSION: The silver nanoparticles were spherical with particle size between 10 to 250 nm. Analysis of the theoretical (Mie light scattering theory) and experimental results showed that the silver NPs in colloidal solution had a diameter of approximately 50 nm. Both colloidal silver NPs showed high anti-bacterial activity against Gram positive and Gram negative bacteria. Glucose nanosilver colloids showed a shorter killing time against most of the tested bacteria which could be due to their nanostructures and uniform size distribution patterns.     

PVP-coated silver nanoparticles and silver ions induce reactive oxygen species, apoptosis and necrosis in THP-1 monocytes

The objective of the present study was to investigate the toxicity of silver nanoparticles (Ag NPs) in vitro. Silver ions (Ag+) have been used in medical treatments for decades whereas Ag NPs have been used in a variety of consumer products within recent years. This study was undertaken to compare the effect of well characterized, PVP-coated Ag NPs (69 nm ± 3 nm) and Ag+ in a human monocytic cell line (THP-1). Characterization of the Ag NPs was conducted in both stock suspension and cell media with or without serum and antibiotics. By using the flowcytometric annexin V/propidium iodide (PI) assay, both Ag NPs and Ag+ were shown to induce apoptosis and necrosis in THP-1 cells depending on dose and exposure time. Furthermore, the presence of apoptosis could be confirmed by the TUNEL method. A number of studies have implicated the production of reactive oxygen species (ROS) in cytotoxicity mediated by NPs. We used the fluorogenic probe, 2′,7′-dichlorofluorescein to assess the levels of intracellular ROS during exposure to Ag NPs and Ag+. A drastic increase in ROS levels could be detected after 6–24 h suggesting that oxidative stress is an important mediator of cytotoxicity caused by Ag NPs and Ag+.     

Recent advances in metal nanoparticles in cancer therapy

Metal nanoparticles (NPs) may have the potential to overcome problems related to conventional chemotherapy. Metal NPs reported to play a beneficial and powerful role in cancer therapy providing better targeting, gene silencing and drug delivery. Functionalised metal NPs with targeting ligands offer a better control of energy deposition in the tumours. Apart from therapeutic benefits, metal NPs are also used as a diagnostic tool for the imaging of cancer cells. Metal NP-based therapeutic systems not only provide simultaneous diagnostic and therapy but also allow controlled and targeted drug release which helps to revolutionise cancer treatment and management. This review addresses the advancement of metal NPs in tumour therapy with a focus on those being explained into clinical settings.     

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.     

The effect of TiO(2) and Ag nanoparticles on reproduction and development of Drosophila melanogaster and CD-1 mice

In the last two decades, nanoparticles (NPs) have found applications in a wide variety of consumer goods. Titanium dioxide (TiO₂) and silver (Ag) NPs are both found in cosmetics and foods, but their increasing use is of concern due to their ability to be taken up by biological systems. While there are some reports of TiO₂ and Ag NPs affecting complex organisms, their effects on reproduction and development have been largely understudied. Here, the effects of orally administered TiO₂ or Ag NPs on reproduction and development in two different model organisms were investigated. TiO₂ NPs reduced the developmental success of CD-1 mice after a single oral dose of 100 or 1000 mg/kg to dams, resulting in a statistically significant increase in fetal deformities and mortality. Similarly, TiO₂ NP addition to food led to a significant progeny loss in the fruit fly, Drosophila, as shown by a decline in female fecundity. Ag NP administration resulted in an increase in the mortality of fetal mice. Similarly in Drosophila, Ag NP feeding led to a significant decrease in developmental success, but unlike TiO₂ NP treatment, there was no decline in fecundity. The distinct response associated with each type of NP likely reflects differences in NP administration as well as the biology of the particular model. Taken together, however, this study warns that these common NPs could be detrimental to the reproductive and developmental health of both invertebrates and vertebrates.     

Metallic gold and bioactive quinacrine hybrid nanoparticles inhibit oral cancer stem cell and angiogenesis by deregulating inflammatory cytokines in p53 dependent manner

Complete eradication of aggressive oral cancer remains a challenge due to the presence of CSCs. They resist conventional chemotherapeutic agents due to their self-renewal, drug efflux, and efficient DNA repair capacity. Here, we formulated a hybrid-nanoparticle (QAuNP) using quinacrine and gold and characterized/investigated its anti-angiogenic and anti-metastatic effect on OSCC-CSCs. QAuNP significantly inhibited cellular proliferation, caused apoptosis in vitro, and disrupted angiogenesis in vivo and tumor regression in xenograft mice model. It not only inhibited crucial angiogenic markers Ang-1, Ang-2 and VEGF but also depleted MMP-2 in H-357-PEMT cells in a p53 and p21-dependent manner. QAuNP also increased the ROS and NO generation in OSCC-CSCs and reduced the mitochondrial membrane potential. It altered the level of inflammatory cytokines IL-6, IL-1β, TNF-α and metastasis-associated markers (CD-44, CD-133) in H-357-PEMT and CM-treated endothelial cells (HUVEC) in p53/p21-dependent manner. Therefore, QAuNP will be a useful therapeutic agent against metastatic OSCC.     

Gold nanoparticles in delivery applications

Gold nanoparticles (AuNPs) provide non-toxic carriers for drug and gene delivery applications. With these systems, the gold core imparts stability to the assembly, while the monolayer allows tuning of surface properties such as charge and hydrophobicity. An additional attractive feature of AuNPs is their interaction with thiols, providing an effective and selective means of controlled intracellular release.     

Cadmium-containing nanoparticles: Perspectives on pharmacology and toxicology of quantum dots

The field of nanotechnology is rapidly expanding with the development of novel nanopharmaceuticals that have potential for revolutionizing medical treatment. The rapid pace of expansion in this field has exceeded the pace of pharmacological and toxicological research on the effects of nanoparticles in the biological environment. The development of cadmium-containing nanoparticles, known as quantum dots, show great promise for treatment and diagnosis of cancer and targeted drug delivery, due to their size-tunable fluorescence and ease of functionalization for tissue targeting. However, information on pharmacology and toxicology of quantum dots needs much further development, making it difficult to assess the risks associated with this new nanotechnology. Further, nanotechnology poses yet another risk for toxic cadmium, which will now enter the biological realm in nano-form. In this review, we discuss cadmium-containing quantum dots and their physicochemical properties at the nano-scale. We summarize the existing work on pharmacology and toxicology of cadmium-containing quantum dots and discuss perspectives in their utility in disease treatment. Finally, we identify critical gaps in our knowledge of cadmium quantum dot toxicity, and how these gaps need to be assessed to enable quantum dot nanotechnology to transit safely from bench to bedside.     

In vitro screening of metal oxide nanoparticles for effects on neural function using cortical networks on microelectrode arrays

Nanoparticles (NPs) may translocate to the brain following inhalation or oral exposures, yet higher throughput methods to screen NPs for potential neurotoxicity are lacking. The present study examined effects of 5 CeO₂ (5– 1288?nm), and 4 TiO₂ (6–142?nm) NPs and microparticles (MP) on network function in primary cultures of rat cortex on 12 well microelectrode array (MEA) plates. Particles were without cytotoxicity at concentrations ≤50?µg/ml. After recording 1?h of baseline activity prior to particle (3–50?µg/ml) exposure, changes in the total number of spikes (TS) and # of active electrodes (#AEs) were assessed 1, 24, and 48?h later. Following the 48?h recording, the response to a challenge with the GABA_A antagonist bicuculline (BIC; 25?µM) was assessed. In all, particles effects were subtle, but 69?nm CeO₂ and 25?nm TiO₂ NPs caused concentration-related decreases in TS following 1?h exposure. At 48?h, 5 and 69?nm CeO₂ and 25 and 31?nm TiO₂ decreased #AE, while the two MPs increased #AEs. Following BIC, only 31?nm TiO₂ produced concentration-related decreases in #AEs, while 1288?nm CeO₂ caused concentration-related increases in both TS and #AE. The results indicate that some metal oxide particles cause subtle concentration-related changes in spontaneous and/or GABA_A receptor-mediated neuronal activity in vitro at times when cytotoxicity is absent, and that MEAs can be used to screen and prioritize nanoparticles for neurotoxicity hazard.     

Expert opinion: Responsive polymer nanoparticles in cancer therapy

Polymeric nanoparticles are emerging as an attractive treatment options for cancer due to their favorable size distribution, drug carrying capacity, and tunable properties. In particular, intelligent nanoparticles that respond to biological cues are of interest because of their ability to provide controlled release at a specific site. Tumor sites display abnormal pH profiles and pathophysiology that can be exploited to provide localized release. In this expert opinion, we discuss passive and active targeting of nanoparticles and several classes of pH-responsive nanoparticles.     

Active targeting schemes for nanoparticle systems in cancer therapeutics

The objective of this review is to outline current major cancer targets for nanoparticle systems and give insight into the direction of the field. The major targeting strategies that have been used for the delivery of therapeutic or imaging agents to cancer have been broken into three sections. These sections are angiogenesis-associated targeting, targeting to uncontrolled cell proliferation markers, and tumor cell targeting. The targeting schemes explored for many of the reported nanoparticle systems suggest the great potential of targeted delivery to revolutionize cancer treatment.     

Biological characterization of folic acid-conjugated poly(H2NPEGCA-co-HDCA) nanoparticles in cellular models

The folate receptor (FR) is a highly selective tumor marker over expressed in many human cancers and it constitutes a useful target for tumor-specific drug delivery. Thus, the conjugation of folic acid to different drugs or drug carriers may enhance the delivery of the therapeutic agent to FR-positive tumor cells. The aim of this study was to investigate the interactions of folate-conjugated polyalkylcyanoacrylate nanoparticles with tumor cells overexpressing the FR. For this purpose, nanoparticles were prepared by nanoprecipitation of the poly[aminopoly(ethylene glycol) cyanoacrylate-co-hexadecyl cyanoacrylate] [poly(H₂NPEGCA-co-HDCA)] copolymer and labeled with the hydrophobic fluorescent dye nile red. Nile red-loaded nanoparticles were then conjugated to folic acid via the PEG terminal amino groups. Four human cancer cell lines were then tested by western blot in order to evaluate the FR expression levels. KB3-1 cell line showed the higher expression level, while MCF-7 cells were taken as a control. After measuring the cytotoxicity of the nanoparticles on these two cell lines, fluorescent folate-nanoparticles were incubated with them and the cellular uptake was evaluated by confocal microscopy and flow cytometry. KB3-1 cells showed a greater nanoparticle internalization, when compared to MCF-7 cells.     

Influence of dextran on the bioadhesive properties of poly(anhydride) nanoparticles

This work describes the bioadhesive properties of poly(methyl vinyl ether-co-maleic anhydride) (Gantrez AN) nanoparticles (NP) associated with various types of dextran (two hydroxyl-functionalized dextrans and one amino-derivative of dextran). The association of dextran to the polymer was performed either prior NP formation or by the attachment of dextran to the surface of the just formed NP. The amount of dextran associated to the nanoparticles was quantified by a HPLC/ELSD method and dextran presence in the nanoparticles was confirmed by IR spectroscopy, ¹H NMR and in vitro agglutination assay. The in vivo bioadhesion study has demonstrated significantly higher adhesive interactions with the gastrointestinal tract of rats for all types of dextran associated nanoparticles compared with control nanoparticles. For nanoparticles associated with the aminated-dextran, the curves of bioadhesion were characterized by a maximum of adhesion just after administration followed by a rapid and constant decline with time. On the contrary, nanoparticles associated to conventional dextrans displayed a maximum bioadhesion between 1 and 3 h post-administration. These results encourage us for further use of these systems for oral delivery of drugs.     

Biological interactions of quantum dot nanoparticles in skin and in human epidermal keratinocytes

Quantum dots nanoparticles have novel optical properties for biomedical applications and electronics, but little is known about their skin permeability and interaction with cells. QD621 are nail-shaped nanoparticles that contain a cadmium/selenide core with a cadmium sulfide shell coated with polyethylene glycol (PEG) and are soluble in water. QD were topically applied to porcine skin flow-through diffusion cells to assess penetration at 1 microM, 2 microM and 10 microM for 24 h. QD were also studied in human epidermal keratinocytes (HEK) to determine cellular uptake, cytotoxicity and inflammatory potential. Confocal microscopy depicted the penetration of QD621 through the uppermost stratum corneum (SC) layers of the epidermis and fluorescence was found primarily in the SC and near hair follicles. QD were found in the intercellular lipid bilayers of the SC by transmission electron microscopy (TEM). Inductively coupled plasma-optical emission spectroscopy (ICP-OES) analysis for cadmium (Cd) and fluorescence for QD both did not detect Cd nor fluorescence signal in the perfusate at any time point or concentration. In HEK, viability decreased significantly (p<0.05) from 1.25 nM to 10 nM after 24 h and 48 h. There was a significant increase in IL-6 at 1.25 nM to 10 nM, while IL-8 increased from 2.5 nM to 10 nM after 24 h and 48 h. TEM of HEK treated with 10 nM of QD621 at 24 h depicted QD in cytoplasmic vacuoles and at the periphery of the cell membranes. These results indicate that porcine skin penetration of QD621 is minimal and limited primarily to the outer SC layers, yet if the skin were damaged allowing direct QD exposure to skin or keratinocytes, an inflammatory response could be initiated.     

Platinum complexes of curcumin delivered by dual-responsive polymeric nanoparticles improve chemotherapeutic efficacy based on the enhanced anti-metastasis activity and reduce side effects

Platinum-based chemotherapy is used for non-small cell lung cancer (NSCLC). However, it has side effects and minimum efficacy against lung cancer metastasis. In this study, platinum–curcumin complexes were loaded into pH and redox dual-responsive nanoparticles (denoted as Pt–CUR@PSPPN) to facilitate intracellular release and synergistic anti-cancer effects. Pt–CUR@PSPPN was prepared by a nano-precipitation method and had a diameter of ∼100 nm. The nanoparticles showed increased anti-cancer effects both in vivo and in vitro. In addition, Pt–CUR@PSPPN blocked PI3K/AKT signal transduction pathway and inhibited MMP2 and VEGFR2, resulting in enhanced anti-metastatic activity. Furthermore, reduced side effects were also observed. In conclusion, Pt–CUR@PSPPN provided a novel and attractive therapeutic strategy for NSCLC.