Iron oxide nanoparticles exert inhibitory effects on N-Bis(2-hydroxypropyl)nitrosamine (DHPN)-induced lung tumorigenesis in rats.

Iron oxide nanoparticles (magnetite) have been widely used in industry and medicine. However, the safety assessment of magnetite has not been fully completed. The present study was conducted to assess effects of magnetite on carcinogenic activity, using a medium-term bioassay protocol. A total of 100 male Fischer 344 rats, 6 weeks old, were randomly divided into 5 groups of 20 animals each, and given a basal diet and drinking water containing 0 or 0.1% of N-bis(2-hydroxypropyl)nitrosamine (DHPN) for 2 weeks. Two weeks later, the rats were intratracheally instilled magnetite 7 times at an interval of 4 weeks, at the doses of 0, 1.0 or 5.0 mg/kg body weight, and sacrificed at the end of the experimental period of 30 weeks. The multiplicities of macroscopic lung nodules and histopathologically diagnosed bronchiolo-alveolar hyperplasia, induced by DHPN, were both significantly decreased by the high dose of magnetite. The expression of minichromosome maintenance (MCM) protein 7 in non-tumoral alveolar epithelial cells, and the number of CD163-positive macrophages in tumor nodules were both significantly reduced by magnetite. It is suggested that magnetite exerts inhibitory effects against DHPN-induced lung tumorigenesis, by the reduction of alveolar epithelial proliferation and the M2 polarization of tumor-associated macrophages.

Comparative Evaluation of Sucrosomial Iron and Iron Oxide Nanoparticles as Oral Supplements in Iron Deficiency Anemia in Piglets.

Iron deficiency is the most common mammalian nutritional disorder. However, among mammalian species iron deficiency anemia (IDA), occurs regularly only in pigs. To cure IDA, piglets are routinely injected with high amounts of iron dextran (FeDex), which can lead to perturbations in iron homeostasis. Here, we evaluate the therapeutic efficacy of non-invasive supplementation with Sucrosomial iron (SI), a highly bioavailable iron supplement preventing IDA in humans and mice and various iron oxide nanoparticles (IONPs). Analysis of red blood cell indices and plasma iron parameters shows that not all iron preparations used in the study efficiently counteracted IDA comparable to FeDex-based supplementation. We found no signs of iron toxicity of any tested iron compounds, as evaluated based on the measurement of several toxicological markers that could indicate the occurrence of oxidative stress or inflammation. Neither SI nor IONPs increased hepcidin expression with alterations in ferroportin (FPN) protein level. Finally, the analysis of the piglet gut microbiota indicates the individual pattern of bacterial diversity across taxonomic levels, independent of the type of supplementation. In light of our results, SI but not IONPs used in the experiment emerges as a promising nutritional iron supplement, with a high potential to correct IDA in piglets.

A combinatorial approach to modulate microenvironment toward regeneration and repair after spinal cord injury in rats.

Traumatic spinal cord injury (SCI) is a devastating condition of CNS which leads to loss of sensory as well as motor functions. Secondary damage after SCI initiates cascade of events that creates an inhibitory milieu for axonal growth and repair. Combinatorial therapies are the hope to attenuate secondary injury progression and make the microenvironment growth and repair friendly for the neurons. We fabricated gelatin- genipin hydrogel system which was impregnated with IONPs and injected at the lesion site in a clinically relevant contusion rat model of SCI. 24 h later, the rats were exposed to magnetic fields (17.96 µT, 50 Hz uniform EMF) for 2 h/day for 5 weeks. A significant (P < 0.001) improvement in Basso, Beattie and Bresnahan (BBB) locomotor score, amplitude and threshold of spinally mediated reflexes and motor and somatosensory evoked potentials (MEP & SSEP) was observed following IONPs implantation and EMF exposure. Moreover, retrograde tracing showed a higher level of neuronal connectivity and survival after the intervention. There was also a reduction in activated microglia and lesion volume which attenuate secondary damage as evident by reduction in the scaring following intervention for 5 weeks. Moreover, we observed increase in the neuronal growth cone marker, GAP-43, growth promoting neurotrophins (GDNF, BDNF & NT-3) and reduction in the inhibitory molecule (Nogo-A) after this combinatorial therapy. We obsrvered that a significant improvement in behavioral, electrophysiological and morphological parameters was due to an alteration in neurotrophin levels, reduction in activated microglia and increase in GAP-43 expression after the combinatorial therapy. We propose that implantation of IONPs embedded gelatin-genipin hydrogel system along with MF exposure modulated the microenvironment, making it conducive for neural repair and regeneration.

In vitro hyperthermic effect of magnetic fluid on cervical and breast cancer cells.

Self-regulating temperature-controlled nanoparticles such as Mn-Zn ferrite nanoparticles based magnetic fluid can be a better choice for magnetic fluid hyperthermia because of its controlled regulation of hyperthermia temperature window of 43-45 °C. To test this hypothesis magnetic fluid with said properties was synthesized, and its effect on cervical and breast cancer cell death was studied. We found that the hyperthermia window of 43-45 °C was maintained for one hour at the smallest possible concentration of 0.35 mg/mL without altering the magnetic field applicator parameters. Their hyperthermic effect on HeLa and MCF7 was investigated at the magnetic field of 15.3 kA/m and frequency 330 kHz, which is close to the upper safety limit of 5 * 109 A/m s. We have tested the cytotoxicity of synthesized Mn-Zn ferrite fluid using MTT assay and the results were validated by trypan blue dye exclusion assay that provides the naked eye microscopic view of actual cell death. Since cancer cells tend to resist treatment and show re-growth, we also looked into the effect of multiple sessions hyperthermia using a 24 h window till 72 h using trypan blue assay. The multiple sessions of hyperthermia showed promising results, and it indicated that a minimum of 3 sessions, each of one-hour duration, is required for the complete killing of cancer cells. Moreover, to simulate an in vivo cellular environment, a phantom consisting of magnetic nanoparticles dispersed in 1 and 5% agarose gel was constituted and studied. These results will help to decide the magnetic fluid based hyperthermic therapeutic strategies using temperature-sensitive magnetic fluid.

New insights on improved growth and biogas production potential of Chlorella pyrenoidosa through intermittent iron oxide nanoparticle supplementation.

In the present work, the effect of α-Fe2O3-nanoparticles (IONPs) supplementation at varying doses (0, 10, 20 and, 30 mg L-1) at the intermittent stage (after 12th day of growth period) was studied on the growth and biogas production potential of Chlorella pyrenoidosa. Significant enhancements in microalgae growth were observed with all the tested IONPs doses, the highest (2.94 ± 0.01 g L-1) being at 20 mg L-1. Consequently, the composition of the biomass was also improved. Based on the precedent determinations, theoretical chemical oxygen demand (CODth) as well as theoretical and stoichiometric methane potential (TMP, and SMP) were also estimated. The CODth, TMP, SMP values indicated IONPs efficacy for improving biogas productivity. Further, the biochemical methane potential (BMP) test was done for IONPs supplemented biomass. The BMP test revealed up to a 25.14% rise in biogas yield (605 mL g-1 VSfed) with 22.4% enhanced methane content for 30 mg L-1 IONPs supplemented biomass over control. Overall, at 30 mg L-1 IONPs supplementation, the cumulative enhancements in biomass, biogas, and methane content proffered a net rise of 98.63% in biomethane potential (≈ 2.86 × 104 m3 ha-1 year-1) compared to control. These findings reveal the potential of IONPs in improving microalgal biogas production.

Cancer therapy with iron oxide nanoparticles: Agents of thermal and immune therapies.

Significant research and preclinical investment in cancer nanomedicine has produced several products, which have improved cancer care. Nevertheless, there exists a perception that cancer nanomedicine 'has not lived up to its promise' because the number of approved products and their clinical performance are modest. Many of these analyses do not consider the long clinical history and many clinical products developed from iron oxide nanoparticles. Iron oxide nanoparticles have enjoyed clinical use for about nine decades demonstrating safety, and considerable clinical utility and versatility. FDA-approved applications of iron oxide nanoparticles include cancer diagnosis, cancer hyperthermia therapy, and iron deficiency anemia. For cancer nanomedicine, this wealth of clinical experience is invaluable to provide key lessons and highlight pitfalls in the pursuit of nanotechnology-based cancer therapeutics. We review the clinical experience with systemic liposomal drug delivery and parenteral therapy of iron deficiency anemia (IDA) with iron oxide nanoparticles. We note that the clinical success of injectable iron exploits the inherent interaction between nanoparticles and the (innate) immune system, which designers of liposomal drug delivery seek to avoid. Magnetic fluid hyperthermia, a cancer therapy that harnesses magnetic hysteresis heating is approved for treating humans only with iron oxide nanoparticles. Despite its successful demonstration to enhance overall survival in clinical trials, this nanotechnology-based thermal medicine struggles to establish a clinical presence. We review the physical and biological attributes of this approach, and suggest reasons for barriers to its acceptance. Finally, despite the extensive clinical experience with iron oxide nanoparticles new and exciting research points to surprising immune-modulating potential. Recent data demonstrate the interactions between immune cells and iron oxide nanoparticles can induce anti-tumor immune responses. These present new and exciting opportunities to explore additional applications with this venerable technology. Clinical applications of iron oxide nanoparticles present poignant case studies of the opportunities, complexities, and challenges in cancer nanomedicine. They also illustrate the need for revised paradigms and multidisciplinary approaches to develop and translate nanomedicines into clinical cancer care.

Bio-synthesized iron oxide nanoparticles for cancer treatment.

Various living organisms, such as bacteria, plants, and animals can synthesize iron oxide nanoparticles (IONP). The mechanism of nanoparticle (NP) formation is usually described as relying on the reduction of ferric/ferrous iron ions into crystallized nanoparticulate iron that is surrounded by an organic stabilizing layer. The properties of these NP are characterized by a composition made of different types of iron oxide whose most stable and purest one appears to be maghemite, by a size predominantly comprised between 5 and 380 nm, by a crystalline core, by a surface charge which depends on the nature of the material coating the iron oxide, and by certain other properties such as a sterility, stability, production in mass, absence of aggregation, that have apparently only been studied in details for IONP synthesized by magnetotactic bacteria, called magnetosomes. In the majority of studies, bio-synthesized IONP are described as being biocompatible and as not inducing cytotoxicity towards healthy cells. Anti-tumor activity of bio-synthesized IONP has mainly been demonstrated in vitro, where this type of NP displayed cytotoxicity towards certain tumor cells, e.g. through the anti-tumor activity of IONP coating or through IONP anti-oxidizing property. Concerning in vivo anti-tumor activity, it was essentially highlighted for magnetosomes administered in different types of glioblastoma tumors (U87-Luc and GL-261), which were exposed to a series of alternating magnetic field applications, resulting in mild hyperthermia treatments at typical temperatures of 41-45 °C, leading to the full disappearance of these tumors without any observable side effects.

Multifunctional magnetic iron oxide nanoparticles: an advanced platform for cancer theranostics.

Multifunctional magnetic nanoparticles and derivative nanocomposites have aroused great concern for multimode imaging and cancer synergistic therapies in recent years. Among the rest, functional magnetic iron oxide nanoparticles (Fe3O4 NPs) have shown great potential as an advanced platform because of their inherent magnetic resonance imaging (MRI), biocatalytic activity (nanozyme), magnetic hyperthermia treatment (MHT), photo-responsive therapy and drug delivery for chemotherapy and gene therapy. Magnetic Fe3O4 NPs can be synthesized through several methods and easily surface modified with biocompatible materials or active targeting moieties. The MRI capacity could be appropriately modulated to induce response between T1 and T2 modes by controlling the size distribution of Fe3O4 NPs. Besides, small-size nanoparticles are also desired due to the enhanced permeation and retention (EPR) effect, thus the imaging and therapeutic efficiency of Fe3O4 NP-based platforms can be further improved. Here, we firstly retrospect the typical synthesis and surface modification methods of magnetic Fe3O4 NPs. Then, the latest biomedical application including responsive MRI, multimodal imaging, nanozyme, MHT, photo-responsive therapy and drug delivery, the mechanism of corresponding treatments and cooperation therapeutics of multifunctional Fe3O4 NPs are also be explained. Finally, we also outline a brief discussion and perspective on the possibility of further clinical translations of these multifunctional nanomaterials. This review would provide a comprehensive reference for readers to understand the multifunctional Fe3O4 NPs in cancer diagnosis and treatment.

Biotechnological approach to induce human fibroblast apoptosis using superparamagnetic iron oxide nanoparticles.

Cancer-Associated Fibroblasts (CAFs) contribute to tumour progression and have received significant attention as a therapeutic target. These cells produce growth factors, cytokines and chemokines, stimulating cancer cell proliferation and inhibiting their apoptosis. Recent advances in drug delivery have demonstrated a significant promise of iron oxide nanoparticles in clinics as theranostic agents, mainly due to their magnetic properties. Here, we designed superparamagnetic iron oxide nanoparticles (SPIONs) to induce apoptosis of human fibroblasts. SPIONs were synthesized via co-precipitation method and coated with sodium citrate (SPION_Cit). We assessed the intracellular uptake of SPIONs by human fibroblast cells, as well as their cytotoxicity and ability to induce thermal effects under the magnetic field. The efficiency and time of nanoparticle internalization were assessed by Prussian Blue staining, flow cytometry and transmission electron microscopy. SPIONs_Cit were detected in the cytoplasm of human fibroblasts 15 min after in vitro exposure, entering into cells mainly via endocytosis. Analyses through Cell Titer Blue assay, AnnexinV-fluorescein isothiocyanate (FITC) and propidium iodide (PI) cellular staining demonstrated that concentrations below 8 × 10-2 mg/mL of SPIONs_Cit did not alter cell viability of human fibroblast. Furthermore, it was also demonstrated that SPIONs_Cit associated with alternating current magnetic field were able to induce hyperthermia and human fibroblast cell death in vitro, mainly through apoptosis (83.5%), activating caspase 8 (extrinsic apoptotic via) after a short exposure period. Collectively these findings suggest that our nanoplatform is biocompatible and can be used for therapeutic purposes in human biological systems, such as inducing apoptosis of CAFs.

Using magnetic particle imaging systems to localize and guide magnetic hyperthermia treatment: tracers, hardware, and future medical applications.

Magnetic fluid hyperthermia (MFH) treatment makes use of a suspension of superparamagnetic iron oxide nanoparticles, administered systemically or locally, in combination with an externally applied alternating magnetic field, to ablate target tissue by generating heat through a process called induction. The heat generated above the mammalian euthermic temperature of 37°C induces apoptotic cell death and/or enhances the susceptibility of the target tissue to other therapies such as radiation and chemotherapy. While most hyperthermia techniques currently in development are targeted towards cancer treatment, hyperthermia is also used to treat restenosis, to remove plaques, to ablate nerves and to alleviate pain by increasing regional blood flow. While RF hyperthermia can be directed invasively towards the site of treatment, non-invasive localization of heat through induction is challenging. In this review, we discuss recent progress in the field of RF magnetic fluid hyperthermia and introduce a new diagnostic imaging modality called magnetic particle imaging that allows for a focused theranostic approach encompassing treatment planning, treatment monitoring and spatially localized inductive heating.

A strategy for iron oxide nanoparticles to adhere to the neuronal membrane in the substantia nigra of mice.

Effective attachment of magnetic nanoparticles to neuronal membranes has far-reaching significance in activating ion channels and treating neurodegenerative diseases. Superparamagnetic iron oxide nanoparticles (SPIONs) synthesized by the polyol pyrolysis method have the advantages of rich surface functional groups, excellent magnetic properties, controllable particle size and water dispersibility. We propose that perfusion of biotin into the targeted brain area should be initially performed because it tends to be adsorbed by cell membranes, followed by injection of streptavidin (SA)-modified SPIONs into the same area of the brain. By means of the strong binding force between SA and biotin, the SPIONs may subsequently adhere to the cell surfaces in the brain area. In this work, fluorescein isothiocyanate-streptavidin (FITC-SA) was modified on the surface of polyethylene imine (PEI)-SPIONs by the EDC-NHS method and stereotaxically injected into the biotin-supplemented substantia nigra of mice. The combination of fluorescence detection with transmission electron microscopy (TEM) confirmed that FITC-SA/PEI-SPIONs adhered to neuronal membranes in the substantia nigra of mice 24 h after injection. The results show that our strategy can promote the attachment of SPIONs to neuronal membranes.