Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Physicochemical Characterization.

The objective of this study was to evaluate physicochemical equivalence between brand (i.e., Ferrlecit) and generic sodium ferric gluconate (SFG) in sucrose injection by conducting a series of comparative in vitro characterizations using advanced analytical techniques. The elemental iron and carbon content, thermal properties, viscosity, particle size, zeta potential, sedimentation coefficient, and molecular weight were determined. There was no noticeable difference between brand and generic SFG in sucrose injection for the above physical parameters evaluated, except for the sedimentation coefficient determined by sedimentation velocity analytical ultracentrifugation (SV-AUC) and molecular weight by asymmetric field flow fractionation-multi-angle light scattering (AFFF-MALS). In addition, brand and generic SFG complex products showed comparable molecular weight distributions when determined by gel permeation chromatography (GPC). The observed minor differences between brand and generic SFG, such as sedimentation coefficient, do not impact their biological activities in separate studies of in vitro cellular uptake and rat biodistribution. Coupled with the ongoing clinical study comparing the labile iron level in healthy volunteers, the FDA-funded post-market studies intended to illustrate comprehensive surveillance efforts ensuring safety and efficacy profiles of generic SFG complex in sucrose injection, and also to shed new light on the approval standards on generic parenteral iron colloidal products.

p53-competent cells and p53-deficient cells display different susceptibility to oxygen functionalized graphene cytotoxicity and genotoxicity.

Due to the distinctive physical, electrical, and chemical properties of graphene nanomaterials, numerous efforts pursuing graphene-based biomedical and industrial applications are underway. Oxidation of pristine graphene surfaces mitigates its otherwise hydrophobic characteristic thereby improving its biocompatibility and functionality. Yet, the potential widespread use of oxidized graphene derivatives raises concern about adverse impacts on human health. The p53 tumor suppressor protein maintains cellular and genetic stability after toxic exposures. Here, we show that p53 functional status correlates with oxygen functionalized graphene (f-G) cytotoxicity and genotoxicity in vitro. The f-G exposed p53-competent cells, but not p53-deficient cells, initiated G0 /G1 phase cell cycle arrest, suppressed reactive oxygen species, and entered apoptosis. There was p53-dependent f-G genotoxicity evident as increased structural chromosome damage, but not increased gene mutation or chromatin loss. In conclusion, the cytotoxic and genotoxic potential for f-G in exposed cells was dependent on the p53 functional status. These findings have broad implications for the safe and effective implementation of oxidized graphene derivatives into biomedical and industrial applications. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Magnetic nanoparticles as contrast agents in biomedical imaging: recent advances in iron- and manganese-based magnetic nanoparticles.

Improvements in diagnostic measures for biomedical applications have been investigated in various studies for better interpretations of biological abnormalities and several medical conditions. The use of imaging techniques, such as magnetic resonance imaging (MRI), is widespread and becoming a standard procedure for such specialized applications. A major avenue being studied in MRI is the use of magnetic nanoparticles (NPs) as contrast agents (CAs). Among various approaches, current research also incorporates use of superparamagnetic iron oxide NPs and manganese-based NPs with biocompatible coatings for improved stability and reduced biodegradation when exposed to a biological environment. In this review, recent advances with these types of magnetic NPs and their potential use as CAs in MRI are reported, as well as new insights into the selectivity and cellular transport mechanism that occurs following injection.

Neurotoxicity of nanoscale materials.

Nanotechnology has been applied in consumer products and commercial applications, showing a significant impact on almost all industries and all areas of society. Significant evidence indicates that manufactured nanomaterials and combustion-derived nanomaterials elicit toxicity in humans exposed to these nanomaterials. The interaction of the engineered nanomaterials with the nervous system has received much attention in the nanotoxicology field. In this review, the biological effects of metal, metal oxide, and carbon-based nanomaterials on the nervous system are discussed from both in vitro and in vivo studies. The translocation of the nanoparticles through the blood-brain barrier or nose to brain via the olfactory bulb route, oxidative stress, and inflammatory mechanisms of nanomaterials are also reviewed.

Toxicity and efficacy of carbon nanotubes and graphene: the utility of carbon-based nanoparticles in nanomedicine.

Carbon-based nanomaterials have attracted great interest in biomedical applications such as advanced imaging, tissue regeneration, and drug or gene delivery. The toxicity of the carbon nanotubes and graphene remains a debated issue although many toxicological studies have been reported in the scientific community. In this review, we summarize the biological effects of carbon nanotubes and graphene in terms of in vitro and in vivo toxicity, genotoxicity and toxicokinetics. The dose, shape, surface chemistry, exposure route and purity play important roles in the metabolism of carbon-based nanomaterials resulting in differential toxicity. Careful examination of the physico-chemical properties of carbon-based nanomaterials is considered a basic approach to correlate the toxicological response with the unique properties of the carbon nanomaterials. The reactive oxygen species-mediated toxic mechanism of carbon nanotubes has been extensively discussed and strategies, such as surface modification, have been proposed to reduce the toxicity of these materials. Carbon-based nanomaterials used in photothermal therapy, drug delivery and tissue regeneration are also discussed in this review. The toxicokinetics, toxicity and efficacy of carbon-based nanotubes and graphene still need to be investigated further to pave a way for biomedical applications and a better understanding of their potential applications to humans.

Single-walled carbon nanotubes as specific targeting and Raman spectroscopic agents for detection and discrimination of single human breast cancer cells.

Raman active nano-complex agents based on single-walled carbon nanotubes (SWCNTs) are prepared and used for the swift and specific detection of breast cancer cells. SWCNTs are functionalized to bond covalently with the anti-epithelial cell adhesion molecule (anti-EpCAM) antibody, which is specific to the highly expressed EpCAM antigen on the surface of breast cancer cells (MCF-7), but not on normal cells. The Raman nano-complexes demonstrate excellent ability to detect in vitro single breast cancer cells (MCF-7) and discriminate between them and normal fibroblast cells during the first 30 min of the targeting process. Raman linearity scanning is collected from a monolayer cell mixture, including both cancer cells and normal cells incubated with anti-EpCAM-SWCNTs, using a 633-nm laser excitation. The results shows that the Raman signal collected from targeted MCF-7 cells is extremely high, whereas there is little signal from the normal cells.

Iron oxide nanoparticle-based radio-frequency thermotherapy for human breast adenocarcinoma cancer cells.

Iron oxide nanoparticles (IONPs) with diameters of 15, 25, and 41 nm were evaluated as mediators of thermal cytotoxicity under radio-frequency (RF) exposure. The 25 nm IONPs were found to be the most efficient of the three in killing cancer cells at 350 kHz low-frequency RF irradiation. However, at a higher frequency of 13.56 MHz, 15 nm IONPs produced the highest percentage of cell death. Moreover, the killing effect was concentration-dependent in that a higher concentration of IONPs resulted in increased cellular death. Size-dependent internalization of IONPs in MCF-7 cells was quantified by using inductively coupled-plasma mass spectrometry (ICP-MS). Dark-field microscopy and transmission electron microscopy (TEM) revealed that MCF-7 cells internalize IONPs through endocytosis after 24 hours of incubation. In addition, after RF treatment, the cancer cells underwent the apoptosis process, and the level of reactive oxygen species (ROS) increased significantly after hyperthermia. Scanning electron microscopy (SEM) and TEM further established that the ultrastructure morphological changes in the cancer cells originated from the apoptosis process.

Multifunctional magnetic nanoparticles for synergistic enhancement of cancer treatment by combinatorial radio frequency thermolysis and drug delivery.

Few-layer, carbon-coated, iron (C/Fe) magnetic nanoparticles (MNPs) were synthesized with controlled sizes ranging from 7 to 9 nm. The additional loading of two anti-cancer drugs, doxorubicin and erlotinib, was achieved through - stacking onto the carbon shells. Controlled release of the drugs was successfully triggered by radio frequency (RF) heating or pH variation. Based on the experimental results, C/Fe MNPs act as heat-inducing agents and are able to thermally destroy cancer cells when RF is applied. It was found that the combination of anti-cancer drugs (in particular a low dose of doxorubicin) and RF treatment demonstrates a synergistic effect in inducing cell death in pancreatic cancer cells. Our findings demonstrate that MNPs can be used as highly efficient multimodal nanocarrier agents for an integrated approach to cancer treatment involving triggered delivery of antineoplastic drugs and RF-induced thermal therapy.

Raman spectroscopy as a detection and analysis tool for in vitro specific targeting of pancreatic cancer cells by EGF-conjugated, single-walled carbon nanotubes.

Single-walled carbon nanotubes (SWCNTs) were covalently linked to epidermal growth factor (EGF) proteins through an esterification process that was found to be responsible for the docking of SWCNTs on the human pancreatic cancer cells (PANC-1) surface, thus providing a mechanism for the enhanced delivery and internalization of the nanotubes. Micro Raman spectroscopy and enzyme-linked immunosorbent assay were used to evaluate the delivery process and kinetics of the SWCNTs. In vitro studies indicated that the delivery kinetics of SWCNT-EGF conjugates, at a concentration of 85 µg ml(-1), to the PANC-1 cell surfaces was significant in the first 30 min of incubation, but reached a plateau with time in accordance with the establishment of equilibrium between the association and the dissociation of EGF with the cell receptors. SWCNT-EGF conjugates could act as strong thermal ablation agents and could induce higher percentages of cellular death compared with the nontargeted SWCNTs alone.

Ethylenediamine functionalized-single-walled nanotube (f-SWNT)-assisted in vitro delivery of the oncogene suppressor p53 gene to breast cancer MCF-7 cells.

A gene delivery concept based on ethylenediamine-functionalized single-walled carbon nanotubes (f-SWCNTs) using the oncogene suppressor p53 gene as a model gene was successfully tested in vitro in MCF-7 breast cancer cells. The f-SWCNTs-p53 complexes were introduced into the cell medium at a concentration of 20 µg mL(-1) and cells were exposed for 24, 48, and 72 hours. Standard ethidium bromide and acridine orange assays were used to detect apoptotic cells and indicated that a significantly larger percentage of the cells (approx 40%) were dead after 72 hours of exposure to f-SWCNTs-p53 as compared to the control cells, which were exposed to only p53 or f-SWCNTs, respectively. To further support the uptake and expression of the genes within the cells, green fluorescent protein-tagged p53, attached to the f-SWCNTs was added to the medium and the complex was observed to be strongly expressed in the cells. Moreover, caspase 3 activity was found to be highly enhanced in cells incubated with the f-SWCNTs-p53 complex, indicating strongly induced apoptosis. This system could be the foundation for novel gene delivery platforms based on the unique structural and morphological properties of multi-functional nanomaterials.

Nanostructural materials increase mineralization in bone cells and affect gene expression through miRNA regulation.

We report that several nanomaterials induced enhanced mineralization (increased numbers and larger areas of mineral nests) in MC3T3-E1 bone cells, with the highest response being induced by silver nanoparticles (AgNPs). We demonstrate that AgNPs altered microRNA expression resulting in specific gene expression associated with bone formation. We suggest that the identified essential transcriptional factors and bone morphogenetic proteins play an important role in activation of the process of mineralization in bone cells exposed to AgNPs.

Synergistic enhancement of cancer therapy using a combination of carbon nanotubes and anti-tumor drug.

AIM: In previous pharmacological applications, single-wall carbon nanotubes (CNTs) have primarily been explored as potential drug carriers and delivery vehicles. Here, we investigate and demonstrate for the first time, that CNTs can be considered as anti-tumor agents and, when in combination with conventional drugs, can significantly enhance their chemotherapeutic effects. METHOD & MATERIALS: HeLa and human Panc1 cancer cells were treated with CNTs (24 h, 10 and 20 microg/ml), etoposide (6 h, 75 x 10(-6) M) and their combination. The cell viability was controlled by flow cytometry, caspase-3 assay and trypan blue dye. RESULTS: A highly increased anti-tumor activity of the combination of etoposide and CNTs against cancer cells, compared with the administration of etoposide and CNTs alone, is reported. Data provided by viability assays suggest a strong interaction between CNTs and the cellular structures, thereby improving the effectiveness of conventional chemotherapeutic agents. CONCLUSION: We believe this finding could lead to the development of new cancer therapies by carefully selecting the cytostatic drugs and nanostructural materials that, in combination, may provide synergistic curative rates.