Emerging Molecular Receptors for the Specific-Target Delivery of Ruthenium and Gold Complexes into Cancer Cells.

Cisplatin and derivatives are highly effective in the treatment of a wide range of cancer types; however, these metallodrugs display low selectivity, leading to severe side effects. Additionally, their administration often results in the development of chemoresistance, which ultimately results in therapeutic failure. This scenario triggered the study of other transition metals with innovative pharmacological profiles as alternatives to platinum, ruthenium- (e.g., KP1339 and NAMI-A) and gold-based (e.g., Auranofin) complexes being among the most advanced in terms of clinical evaluation. Concerning the importance of improving the in vivo selectivity of metal complexes and the current relevance of ruthenium and gold metals, this review article aims to survey the main research efforts made in the past few years toward the design and biological evaluation of target-specific ruthenium and gold complexes. Herein, we give an overview of the inorganic and organometallic molecules conjugated to different biomolecules for targeting membrane proteins, namely cell adhesion molecules, G-protein coupled receptors, and growth factor receptors. Complexes that recognize the progesterone receptors or other targets involved in metabolic pathways such as glucose transporters are discussed as well. Finally, we describe some complexes aimed at recognizing cell organelles or compartments, mitochondria being the most explored. The few complexes addressing targeted gene therapy are also presented and discussed.

Intratumoral generation of photothermal gold nanoparticles through a vectorized biomineralization of ionic gold.

Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation.

A promising drug delivery candidate (CS-g-PMDA-CYS-fused gold nanoparticles) for inhibition of multidrug-resistant uropathogenic Serratia marcescens.

Antibiotic resistance amongst microbial pathogens is a mounting serious issue in researchers and physicians. Various alternatives to overcome the multidrug-resistant bacterial infections are under search, and biofilm growth inhibition is one of them. In this investigation, a polymeric drug delivery system loaded with multi-serratial drugs to improve the delivery of drugs against urinary tract infection causative Serratia marcescens. The chitosan grafted pyromellitic dianhydride - cysteine (CS-g-PMDA-CYS) was conjugated with AuNPs by using the -SH group of CYS and RF (rifampicin) and INH (isoniazid) were loaded in AuNPs-fused CS-g-PMDA-CYS system. Several physicochemical techniques characterized this fabricated AuNPs/RF/INH/CS-g-PMDA-CYS system. The successful encapsulation of RF and INH in AuNPs-fused CS-g-PMDA-CYS polymer had confirmed, and it observed the loading capacity for RF and INH was 9.02% and 13.12%, respectively. The in vitro drug discharge pattern was perceived high in pH 5.5 compared with pH 7.4. The AuNPs/RF/INH/CS-g-PMDA-CYS escalates 74% of Caenorhabditis elegans survival during Serratia marcescens infection by aiming biofilm development and virulence in S. marcescens. Author postulate that the fabricated system is a promising drug carrier and delivery system for inhibition of multidrug-resistant bacterias like S. marcescens.

Gold induces a pseudo-allergic reaction via MRGPRX2 both in vitro and in vivo.

The traditional mast cell (MC) degranulation pathway is mediated by crossing-linking of high-affinity IgE receptor (FcεRI), whereas a non-traditional, but analogous, pseudo-allergic way was recently reported to occur via Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2). Severe contact hypersensitivity to metallic gold, typically considered non-sensitizing, has been reported. However, whether gold induces IgE-independent allergy remains unclear. Therefore, this study assessed the effects of gold chloride (CA) on MC activation and its relation to MRGPRX2. Our data show that CA acted on MRGPRX2 to increase cellular calcium levels and induced the release of inflammatory mediators in vitro. Compared to Mrgprb2-knockout (KO) mice, CA dose-dependently induced passive cutaneous anaphylaxis (PCA) in wild-type (WT) mice. Furthermore, peritoneal mast cells (MPMCs) were extracted from WT and Mrgprb2-KO mice and stimulated by CA, but only MPMCs from WT mice could be activated. Our results suggest that CA-induced pseudo-allergic responses are MRGPRX2 dependent.

Radio-sensitization efficacy of gold nanoparticles in inhalational nanomedicine and the adverse effect of nano-detachment due to coating inactivation.

Gold nanoparticles (GNPs) are an emerging area of interest in radiation therapy due to their unique radio-sensitizing properties. In the literature, the enhancing capability of GNPs is usually quantified using the metric dose enhancement ratio (DER). Traditionally, the focus of the vast majority of studies has always been on intravenous administration of GNPs. However, recent work showed the potential of using GNP inhalation, rather than intravenous injection, to enhance the dose to the lung. Yet, some of these studies are employing simplistic analytical methods to calculate DER and, thus far, there are no detailed computations of the enhancement profiles therein. Moreover, the coating on the GNP surface can be adversely affected by the large gradient of the radiation dose in the immediate vicinity of GNPs, leading to the rupture of ligands and detachment of GNPs from the surface of the membrane, and hence the loss of its efficacy. In this study, a next-generation deterministic code was used to resolve the DER profile at the interface between the septum, air, and surface of GNPs when they are attached and detached. The results show that the large values of DER in conjunction with the developed hot spots are very effective in lung treatment; on the other hand, coating rupture can lead to significant reduction in DER that may reach 64%. Thus, GNPs can be beneficial in inhalational medicine to treat lung cancer, provided that more comprehensive studies on the characteristics of the coating are addressed to maximize the radio-therapeutic benefit of GNPs.

Assessment of oxidative stress induced by gold nanorods following intra-tracheal instillation in rats.

Gold nanorods (GNRs) are used for their wide variety of applications in various industries. There is a little availability of data related to toxicity and ecological implications of these GNRs. The study evaluated the oxidative stress induction following intra-tracheal instillation of 1 and 5 mg/kg b.w. doses of 10 and 25 nm GNRs by estimating various oxidative stress markers including lipid peroxidation (malondialdehyde; MDA), glutathione (GSH), superoxide dismutase (SOD), catalase and total antioxidant capacity (TAC) after 1 day, 1 week, 1 month, and 3 months post exposure periods. The results have shown increased MDA levels and decreased GSH levels following 1 day and 1 week post exposure periods, indicating induction of oxidative stress. Also, the SOD, catalase and TAC levels were significantly decreased following exposure of both 10 and 25 nm GNRs after 1 day and 1 week after exposures, indicating the inhibition of antioxidant defense mechanisms. Moreover, the 10 nm GNRs at 5 mg/kg dose displayed greater changes in all the estimated parameters, representing dose and size based induction of oxidative stress by GNRs. In contrast, a little change was observed during 1 month and 3 months post exposure periods, may be due to recovery. Finally, the GNRs induced dose-size-dependent oxidative stress induction by various oxidative stress markers following intra-tracheal instillation in rats.

Shave Excision With Keratopigmentation for Limbal Dermoid.

OBJECTIVES: To describe a modified technique of corneal tattooing for concomitant cosmetic rehabilitation in eyes with limbal dermoid. STUDY: Case series. METHODS: Three patients between 12 and 20 years of age with grade I limbal dermoid underwent shave excision with corneal tattooing. All patients had dark brown irides. Chemical keratopigmentation was performed over the bed using 2% gold chloride with 1% hydrazine hydrate as reducing agent to yield a dark brown color. Bandage contact lens was applied. RESULTS: Epithelium over the operated area healed by day 10. Visual acuity was maintained in all eyes with minimal change in keratometry. The dye was well retained in the tattooed area at 1 year. No complications such as infection, pseudopterygium, or local limbal stem-cell deficiency were observed. CONCLUSION: Corneal tattooing along with simple shave excision provides good cosmetic results in cases of limbal dermoids.

Comparative effect of gold nanorods and nanocages for prostate tumor hyperthermia.

Gold nanoparticles have been investigated as photothermal agents, drug delivery carriers, diagnostics, and theranostics. As long-term accumulation of nanoparticles in nontarget tissues is a growing concern, it is vital to establish biodistribution profiles, tumor uptake, and tissue residence times for each nano-based system. This study aimed to investigate the prostate tumor uptake, photothermal therapy mediated macromolecular delivery, acute and chronic biodistribution profiles, and organ residence time differences between two nanoparticles, i.e., gold nanocages and gold nanorods. These particles have tunable surface plasmon resonances in the near infrared, but dissimilar shapes. Gold nanocages and nanorods had very different light to heat transduction efficiencies, with gold nanocages requiring 18.4 times fewer particles and approximately half the gold mass of gold nanorods to achieve the same heating profile given a constant laser intensity. It was also observed that while the photothermal macromolecular delivery enhancements were similar for the two systems when dosed by optical density, the tumoral uptake and biodistribution profiles for each of these shapes differed, with the nanocages residing in the liver, kidneys and spleen for less time than the nanorods. Additionally, it was observed that the nanocages were excreted from the body at a higher percentage of injected dose than the nanorods at both the 7 and 28 day time points. These findings have implications for the use of these constructs in diagnostic and therapeutic applications.

Translocation of gold nanoparticles across the lung epithelial tissue barrier: Combining in vitro and in silico methods to substitute in vivo experiments.

BACKGROUND: The lung epithelial tissue barrier represents the main portal for entry of inhaled nanoparticles (NPs) into the systemic circulation. Thus great efforts are currently being made to determine adverse health effects associated with inhalation of NPs. However, to date very little is known about factors that determine the pulmonary translocation of NPs and their subsequent distribution to secondary organs. METHODS: A novel two-step approach to assess the biokinetics of inhaled NPs is presented. In a first step, alveolar epithelial cellular monolayers (CMLs) at the air-liquid interface (ALI) were exposed to aerosolized NPs to determine their translocation kinetics across the epithelial tissue barrier. Then, in a second step, the distribution to secondary organs was predicted with a physiologically based pharmacokinetic (PBPK) model. Monodisperse, spherical, well-characterized, negatively charged gold nanoparticles (AuNP) were used as model NPs. Furthermore, to obtain a comprehensive picture of the translocation kinetics in different species, human (A549) and mouse (MLE-12) alveolar epithelial CMLs were exposed to ionic gold and to various doses (i.e., 25, 50, 100, 150, 200 ng/cm(2)) and sizes (i.e., 2, 7, 18, 46, 80 nm) of AuNP, and incubated post-exposure for different time periods (i.e., 0, 2, 8, 24, 48, 72 h). RESULTS: The translocation kinetics of the AuNP across A549 and MLE-12 CMLs was similar. The translocated fraction was (1) inversely proportional to the particle size, and (2) independent of the applied dose (up to 100 ng/cm(2)). Furthermore, supplementing the A549 CML with two immune cells, i.e., macrophages and dendritic cells, did not significantly change the amount of translocated AuNP. Comparison of the measured translocation kinetics and modeled biodistribution with in vivo data from literature showed that the combination of in vitro and in silico methods can accurately predict the in vivo biokinetics of inhaled/instilled AuNP. CONCLUSION: Our approach to combine in vitro and in silico methods for assessing the pulmonary translocation and biodistribution of NPs has the potential to replace short-term animal studies which aim to assess the pulmonary absorption and biodistribution of NPs, and to serve as a screening tool to identify NPs of special concern.

Biodistribution of gold nanoparticles in mice and investigation of their possible translocation by nerve uptake around the alveolus.

The effect of nanoparticles in the environment on our health is a cause of concern. The greatest concern with respect to the biological effect of nanoparticles is that they remain in the body and invade tissues, overcoming the protective mechanisms of the body. It is generally believed that nanoparticles invading a living body move into the blood and are carried by the bloodstream to all organs. However, some studies have shown that the inhaled nanoparticles directly translocate to the central nervous system by nerve uptake. Here quantification of the amount of migration of nanoparticles to organs in short time spans (1, 3, and 6 hr) was attempted by animal experiments. Furthermore, the possibility of migration of nanoparticles through the nerves that project around the alveolus, including the nodose ganglion and dorsal root ganglion (DRG), was investigated. Gold (Au) nanoparticles (15 nm) were administered to mice by intratracheal instillation and tail vein injection. After tail vein injection, most nanoparticles were distributed in the liver. After intratracheal instillation, approximately 80% of detected nanoparticles remained in the lungs at 1 hr and were believed to be translocated to digestive organs, including the stomach and intestine, at 3 and 6 hr. With respect to quantification in ganglia, the levels in most samples were lower than the limit of quantification of inductively coupled plasma mass spectrometry (ICP-MS). However, Au nanoparticles were detected in DRG in only some samples of intratracheal instillation. Therefore, this suggests the possibility of translocation of nanoparticles to DRG via nerves.

Size-dependent clearance of gold nanoparticles from lungs of Sprague-Dawley rats after short-term inhalation exposure.

Gold nanoparticles are known to be distributed to many tissues following their oral, inhalation, or intravenous exposure. Information on the biodistribution and clearance of gold nanoparticles from these tissues is, therefore, important to understand their behavior in vivo. To study the effect of size on the biodistribution of gold nanoparticles, Sprague-Dawley rats were exposed by inhalation to small gold nanoparticles (13 nm in diameter on average) at an exposure concentration of 12.8 ± 2.42 µg/m(3), and to large gold nanoparticles (105 nm in diameter on average) at an exposure concentration of 13.7 ± 1.32 µg/m(3). The experimental animals were exposed to the gold nanoparticles and the control animals to fresh air for 5 days (6 h/day), followed by a recovery period of 1, 3, and 28 days in fresh air. None of the exposed animals exhibited any toxic response to the gold nanoparticles. Despite the difference in size, both small and large gold nanoparticles deposited mainly in rat lungs. Their biodistribution from the lungs to secondary target organs was significantly higher with the small compared to the large gold nanoparticles. While the large gold nanoparticles were only found in the blood, the small gold nanoparticles were detected in the liver, spleen, brain, testes, and blood. In addition, the elimination half-life of the small gold nanoparticles from the lungs was significantly shorter than that of the large gold nanoparticles. The present data may, therefore, suggest that the smaller gold nanoparticles are able to translocate from the lungs, the primary exposure organ to extrapulmonary organs at a faster rate than the larger gold nanoparticles and thus confirming previous observations reported in the literature.

Stable oligomeric clusters of gold nanoparticles: preparation, size distribution, derivatization, and physical and biological properties.

Reducing dilute aqueous HAuCl4 with NaSCN under alkaline conditions produces 2-3 nm diameter yellow nanoparticles without the addition of extraneous capping agents. We here describe two very simple methods for producing highly stable oligomeric grape-like clusters (oligoclusters) of these small nanoparticles. The oligoclusters have well-controlled diameters ranging from ∼5 to ∼30 nm, depending mainly on the number of subunits in the cluster. Our first ["delay-time"] method controls the size of the oligoclusters by varying from seconds to hours the delay time between making the HAuCl4 alkaline and adding the reducing agent, NaSCN. Our second ["add-on"] method controls size by using yellow nanoparticles as seeds onto which varying amounts of gold derived from "hydroxylated gold", Na(+)[Au(OH4-x)Clx](-), are added-on catalytically in the presence of NaSCN. Possible reaction mechanisms and a simple kinetic model fitting the data are discussed. The crude oligocluster preparations have narrow size distributions, and for most purposes do not require fractionation. The oligoclusters do not aggregate after ∼300-fold centrifugal-filter concentration, and at this high concentration are easily derivatized with a variety of thiol-containing reagents. This allows rare or expensive derivatizing reagents to be used economically. Unlike conventional glutathione-capped nanoparticles of comparable gold content, large oligoclusters derivatized with glutathione do not aggregate at high concentrations in phosphate-buffered saline (PBS) or in the circulation when injected into mice. Mice receiving them intravenously show no visible signs of distress. Their sizes can be made small enough to allow their excretion in the urine or large enough to prevent them from crossing capillary basement membranes. They are directly visible in electron micrographs without enhancement, and can model the biological fate of protein-like macromolecules with controlled sizes and charges. The ease of derivatizing the oligoclusters makes them potentially useful for presenting pharmacological agents to different tissues while controlling escape of the reagents from the circulation.

Controlled-release systems for metal-based nanomedicine: encapsulated/self-assembled nanoparticles of anticancer gold(III)/platinum(II) complexes and antimicrobial silver nanoparticles.

The therapeutic applications of many anticancer or antimicrobial metal complexes often suffer from low solubility and low stability in physiological conditions or from drug resistance. To circumvent these problems, nanoparticle systems that allow controlled release and specific accumulation in the targeted disease tissue are of advantage for efficient treatment with minimal toxicity. The focus of this Research News is metal-based nanomaterials comprising anticancer gold(III)/platinum(II) complexes or antimicrobial silver, highlighting the controlled-release properties of self-assembled metal systems.

Effects of gold nanoparticles on endotoxin-induced uveitis in rats.

PURPOSE: This study evaluates the effects of the gold nanoparticle in endotoxin-induced uveitis in rats. METHODS: Adult male Wistar rats were divided into five groups: saline + saline, lipopolysaccharide (LPS) + saline, LPS + prednisolone, LPS + gold salt (GS) and LPS + gold nanoparticle (GNP). Two hours after LPS administration, prednisolone acetate 1%, GS, and GNP were topically applied to both eyes of rats and repeated every 6 hours for 24 hours. After 24 hours, rats were anesthetized and aqueous humor was sampled and the irides were removed. Aqueous humor TNF-α, myeloperoxidase activity were determined. Irides oxidative damage and content of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) were determined. RESULTS: The administration of LPS-induced eye inflammatory response characterized by an increase in aqueous humor TNF-α, myeloperoxidase, and by irides oxidative damage. All these parameters were decreased by the administration of GNP. Since the inflammatory response secondary to LPS administration depends, in part, to the activation of the TLR4-NF-κB pathway we demonstrated here that a potential mechanism to explain the GNP effects was the decrease on TLR4 content and NF-κB activation. CONCLUSIONS: These findings suggest that topical GNP decreases intraocular inflammation and oxidative damage by interfering in the TLR4-NF-κB pathway.

In vivo measurements of blood flow in a rat using X-ray imaging technique.

To measure instantaneous velocity fields of venous blood flow in a rat using X-ray particle tracking method. Gold nanoparticles (AuNPs) incorporated chitosan microparticles were applied as biocompatible flow tracers. After intravenous injection of the AuNP-chitosan particles into 7- to 9-week-old male rat vein, X-ray images of particle movement inside the cranial vena cava were consecutively captured. Individual AuNP-chitosan particles in the venous blood flow were clearly observed, and the corresponding velocity vectors were successfully extracted. The measured velocity vectors are in good agreement with the theoretical velocity profile suggested by Casson. This is the first trial to measure blood flow in animals under in vivo conditions with X-ray imaging technique. The results show that X-ray particle tracking technique has a great potential for in vivo measurements of blood flow, which can extend to various biomedical applications related with the diagnosis of circulatory vascular diseases.

Determination of cyanide in blood by electrospray ionization tandem mass spectrometry after direct injection of dicyanogold.

An electrospray ionization tandem mass spectrometric (ESI-MS-MS) method has been developed for the determination of cyanide (CN(-)) in blood. Five microliters of blood was hemolyzed with 50 µL of water, then 5 µL of 1 M tetramethylammonium hydroxide solution was added to raise the pH of the hemolysate and to liberate CN(-) from methemoglobin. CN(-) was then reacted with NaAuCl(4) to produce dicyanogold, Au(CN)(2)(-), that was extracted with 75 µL of methyl isobutyl ketone. Ten microliters of the extract was injected directly into an ESI-MS-MS instrument and quantification of CN(-) was performed by selected reaction monitoring of the product ion CN(-) at m/z 26, derived from the precursor ion Au(CN)(2)(-) at m/z 249. CN(-) could be measured in the quantification range of 2.60 to 260 µg/L with the limit of detection at 0.56 µg/L in blood. This method was applied to the analysis of clinical samples and the concentrations of CN(-) in the blood were as follows: 7.13 ± 2.41 µg/L for six healthy non-smokers, 3.08 ± 1.12 µg/L for six CO gas victims, 730 ± 867 µg for 21 house fire victims, and 3,030 ± 97 µg/L for a victim who ingested NaCN. The increase of CN(-) in the blood of a victim who ingested NaN(3) was confirmed using MS-MS for the first time, and the concentrations of CN(-) in the blood, gastric content and urine were 78.5 ± 5.5, 11.8 ± 0.5, and 11.4 ± 0.8 µg/L, respectively.

[Pemphigus: a review]. / Pemphigus: revue de la littérature.

BACKGROUND: Pemphigus is a rare autoimmune bullous disorder. Numerous treatment regimens have been proposed in the literature. OBJECTIVE: To assess the efficacy and tolerance of treatment regimens proposed in pemphigus vulgaris (PV) and pemphigus foliaceus (PF), from a systematic review of the literature. METHODS: Randomized control trials have been identified using the PubMed and Embase databases up to April 2009. Uncontrolled prospective and retrospective studies have also been analyzed. RESULTS: Eleven randomized control trials having included a total number of 421 patients (377 PV, 44 PF) have been analyzed. Most studies had a limited statistical power due to the rather low number of cases included. Results from ten different treatment regimens have been analyzed: different dosages of prednisone and prednisolone, pulse intravenous dexamethasone, azathioprine, cyclophosphamide, cyclosporine, dapsone, mycophenolate mofetil, plasmapheresis, topical applications of epidermal growth factor (EGF), and intravenous immune globulins (IVIG). Inclusion criteria were: (i) consecutive patients in nine studies, (ii) patients who did not respond to low doses of corticosteroids in one study, and (iii) patients with relapsing type of pemphigus in one study. None of these studies allowed identifying the best effective and well tolerated regimen. Mycophenolate mofetil was more effective than azathioprine for disease control (from one study; n=40; OR=0.72; 95% CI=0.52-0.99). However, no difference in the rate of clinical remission was evidenced between these drugs. Azathioprine and cyclophosphamide seem to have a corticosteroid sparing effect. CONCLUSION: Data from the literature did not allow identifying the best therapeutic regimen, mainly because of the lack of statistical power of most studies. The usefulness of immunosuppressant added to systemic corticosteroids as the first line of treatment is not clearly established.

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.