Magnetic studies of ultrafine CoFe2O4 nanoparticles with different molecular surface coatings.

Surface functionalized ultrafine CoFe2O4 nanoparticles (NPs), with mean diameter ∼5 nm, were investigated by means of DC magnetization and AC susceptibility over the temperature range of 4-400 K. All NPs present the same CoFe2O4 core, with different molecular surface coatings, increasing gradually the number of carbon atoms in the coating layer: glycine (C2H5NO2), alanine (C3H7NO2), aminobutanoic acid (C4H9NO2), aminohexanoic acid (C6H13NO2), and aminododecanoic acid (C12H25NO2). Samples were intentionally fabricated in order to modulate the core-core magnetic dipolar interaction, as the thickness of the coating layer increases with the number of carbon atoms in the coating molecule. The magnetic data of the uncoated CoFe2O4 NPs were also collected for comparison. All investigated CoFe2O4 NPs (coated and uncoated) are in a magnetically blocked state at room temperature as evidenced by ZFC/FC measurements and the presence of hysteresis with ∼700 Oe coercivity. Low temperature magnetization scans show slightly constricted hysteresis loops with coercivity decreasing systematically with a decreasing number of carbon atoms in the coating molecule, possibly resulting from differences in magnetic dipole coupling between NPs. Large thermomagnetic irreversibility, slow monotonic increase in the FC magnetization and non-saturation of the magnetization give evidence for the cluster glass (CG) nature in the CoFe2O4 NPs. The out of phase part (χ'') of AC susceptibility for all samples shows a clear frequency dependent hump which was analyzed to distinguish superparamagnetic (SPM), cluster glass (CG) and spin glass (SG) behavior by using Néel-Arrhenius, Vogel-Fulcher, and power law fittings. These analyses rule out the SPM state and suggest the presence of significant inter-cluster dipolar interaction, giving rise to CG cooperative freezing in the high-temperature region. In the low-temperature range, however, the disordered spins on the nanoparticle's surface play an important role in the formation of the SG-like state, as evidenced by Arrott plots and temperature dependency of dM/dH in the initial magnetization curves. In summary, the magnetic measurements showed that undercooling the system evolves from a SPM state of weakly interacting spin clusters, through the CG state induced by strong dipolar interaction, to the SG state resulting from the frustration of the disordered surface spins.

Engineering Gold Shelled Nanomagnets for Pre-Setting the Operating Temperature for Magnetic Hyperthermia.

This study investigated the fabrication of spherical gold shelled maghemite nanoparticles for use in magnetic hyperthermia (MHT) assays. A maghemite core (14 ± 3 nm) was used to fabricate two samples with different gold thicknesses, which presented gold (g)/maghemite (m) content ratios of 0.0376 and 0.0752. The samples were tested in MHT assays (temperature versus time) with varying frequencies (100-650 kHz) and field amplitudes (9-25 mT). The asymptotic temperatures (T∞) of the aqueous suspensions (40 mg Fe/mL) were found to be in the range of 59-77 °C (naked maghemite), 44-58 °C (g/m=0.0376) and 33-51 °C (g/m=0.0752). The MHT data revealed that T∞ could be successful controlled using the gold thickness and cover the range for cell apoptosis, thereby providing a new strategy for the safe use of MHT in practice. The highest SAR (specific absorption rate) value was achieved (75 kW/kg) using the thinner gold shell layer (334 kHz, 17 mT) and was roughly twenty times bigger than the best SAR value that has been reported for similar structures. Moreover, the time that was required to achieve T∞ could be modeled by changing the thermal conductivity of the shell layer and/or the shape/size of the structure. The MHT assays were pioneeringly modeled using a derived equation that was analytically identical to the Box-Lucas method (which was reported as phenomenological).

Combination of selol nanocapsules and magnetic hyperthermia hinders breast tumor growth in aged mice after a short-time treatment.

Short time treatment with reduced dosages of selol-loaded PLGA nanocapsules (NcSel) combined with magnetic hyperthermia (MHT) is evaluated in aged Erhlich tumor-bearing mice. Clinical, hematological, biochemical, genotoxic and histopathological parameters are assessed during 7 d treatment with NcSel and MHT, separately or combined. The time evolution of the tumor volume is successfully modeled using the logistic mathematical model. The combined therapy comprising NcSel and MHT is able to hinder primary tumor growth and a case of complete tumor remission is recorded. Moreover, no metastasis was diagnosed and the adverse effects are negligible. NcSel plus MHT may represent an effective and safe alternative to cancer control in aged patients. Future clinical trials are encouraged.

Tumor vascular heterogeneity and the impact of subtumoral nanoemulsion biodistribution.

Aim: Investigate the heterogeneous tumor tissue organization and examine how this condition can interfere with the passive delivery of a lipid nanoemulsion in two breast cancer preclinical models (4T1 and Ehrlich). Materials & methods: The authors used in vivo image techniques to follow the nanoemulsion biodistribution and microtomography, as well as traditional histopathology and electron microscopy to evaluate the tumor structural characteristics. Results & conclusion: Lipid nanoemulsion was delivered to the tumor, vascular organization depends upon the subtumoral localization and this heterogeneous organization promotes a nanoemulsion biodistribution to the highly vascular peripherical region. Also, the results are presented with a comprehensive mathematical model, describing the differential biodistribution in two different breast cancer models, the 4T1 and Ehrlich models.

Nanostrategies to Develop Current Antiviral Vaccines.

Infectious diseases are a worldwide concern. They are responsible for increasing the mortality rate and causing economic and social problems. Viral epidemics and pandemics, such as the COVID-19 pandemic, force the scientific community to consider molecules with antiviral activity. A number of viral infections still do not have a vaccine or efficient treatment and it is imperative to search for vaccines to control these infections. In this context, nanotechnology in association with the design of vaccines has presented an option for virus control. Nanovaccines have displayed an impressive immune response using a low dosage. This review aims to describe the advances and update the data in studies using nanovaccines and their immunomodulatory effect against human viruses.

Acute reproductive toxicology after intratesticular injection of silver nanoparticles (AgNPs) in Wistar rats.

This study aimed to evaluate the effects of an intratesticular injection of silver nanoparticles (AgNPs) on reproductive parameters and health of rats, and to evaluate the AgNPs biodistribution in order to develop a nanotechnological contraceptive agent for male animals. Treated animals received 220 µL of AgNPs solution (0.46 µg-Ag/ml) in each testicle and were euthanized: seven, 14, 28, and 56 days after injection. A significant decrease (p < 0.05) in the percentage of motile sperm in D7 (8.8%) was observed, comparing to the control (73.3%), D14 (86.0%), D28 (68.2%), and D56 (90.0%) groups. D7 group also presented a decrease (p < 0.05) in the percentage of normal spermatozoa. Additionally, D7 group showed an increase (p < 0.05) in abnormal midpiece and sperm head morphology compared to the Control group. Seminiferous tubules presented all germline cell types and spermatozoa for all groups. However, D7 group did not present spermatozoa in the epididymis, whereas some spermatozoa and cellular debris were visible in D14 and D28 groups. All animals presented hematological parameters, creatinine, and alanine aminotransferase values within the normal limits for Wistar rats. The percentage of silver found in the liver was always higher than in the other organs analyzed. A pioneering mathematical model is proposed, from which the half-life time of silver in the liver (17 days), spleen (23 days), lungs (30 days), and kidneys (35 days) was extracted. In conclusion, some acute and severe toxic effects were observed in sperm cells following intratesticular injection of AgNPs, although these effects were reversible. No adverse effects to general animal health were observed.

Fluorine-containing graphene quantum dots with a high singlet oxygen generation applied for photodynamic therapy.

Recently, graphene quantum dots (GQDs) have been extensively studied in biomedical areas such as bio-imaging, bio-sensing and photothermal therapy due to their superior optical and physiochemical properties compared to traditional organic biomarkers. Application of GQDs in photodynamic therapy (PDT) has been explored since 2014, but currently the main challenges are inadequate singlet oxygen (1O2) quantum yield (QY), poor solubility and biocompatibility. Herein, we report on the synthesis of a new class of fluorine-containing GQDs (F-GQDs) by an oxidative cutting method using fluorinated graphite as the raw material. The as-synthesized F-GQD sample demonstrates an average particle size of 2.1 nm with a fluorine doping content of 1.43%. The F-GQDs have a better water solubility and biocompatibility than the GQDs, and emit strong green fluorescence at 365 nm excitation with a relative fluorescence QY of 13.72%. Moreover, the fluorescence imaging effect as well as photodynamic activity was successfully tested in both an in vitro HepG2 cell line model and a 3D multicellular spheroid model, the latter of which mimics the tumour microenvironment. Further studies using UV-visible spectroscopy to monitor the degradation of water-soluble 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABDA) demonstrate that the F-GQD sample generates 1O2 efficiently (QY = 0.49) under visible light irradiation. Compared to non-fluorinated GQDs, the as-reported F-GQDs appear to be a more promising photosensitizer for image-guided PDT.

Fluorine and Nitrogen Co-Doped Carbon Dot Complexation with Fe(III) as a T1 Contrast Agent for Magnetic Resonance Imaging.

Commercial gadolinium-based materials have been widely used as contrast agents for magnetic resonance imaging (MRI), but the high toxicity of leaking free Gd3+ ions still raises biosafety concerns. Here, we develop a novel, safe, and efficient MRI contrast agent based on a stable Fe(III) complex of fluorine and nitrogen co-doped carbon dots (F,N-CDs) that was prepared from glucose and levofloxacin by a simple microwave-assisted thermal decomposition method. The obtained Fe3+@F,N-CD complex exhibits higher longitudinal relaxivity ( r1 = 5.79 mM-1·s-1) than that of the control samples of the Fe3+@CD complex ( r1 = 4.23 mM-1 s-1) and free Fe3+ ( r1 = 1.59 mM-1 s-1) in aqueous solution, as assessed by a 1.5 T NMR analyzer. More importantly, the Fe3+@F,N-CD complex is very stable with a large coordination constant of 1.06 × 107 in aqueous medium. While incubated with HeLa cells, the Fe3+@F,N-CD complex shows clear MR images, demonstrating that it has potential to be an excellent MRI contrast agent. Furthermore, in vivo MRI experiments indicate that the Fe3+@F,N-CD complex provides high-resolution MRI pictures of 4T1 tumor bearing BALB/c mice 15 min after injection and can be completely excreted 2 h after administration. No cytotoxicity was observed with F,N-CDs and Fe concentration up to 0.2 mg/mL and 0.3 mM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay, respectively. The possible mechanism of the enhanced MRI effect of the Fe3+@F,N-CD complex is therefore proposed. The extremely low toxicity, high r1 relaxivity, strong photoluminescence, and low synthetic cost enable the Fe3+@F,N-CD complex to be a safe and promising T1-weighted MRI contrast agent for clinical applications.

In vivo toxicological evaluation of polymer brush engineered nanoceria: impact of brush charge.

Nanoceria has a broad variety of industrial and pharmacological applications due to its antioxidant activity. Nanoceria can be modified by surface coating with polyelectrolyte brushes. Brushes can increase the surface charge of nanoceria, providing greater aqueous stability while reducing agglomeration. However, surface-coating also behaves as a barrier around nanoceria, affecting its redox equilibrium and, hence, its biological and toxicological properties. In the present study, we examined whether bare nanoceria (CeO2; 80-150 nm) and nanoceria modified by surface polymer brush, using negatively charged polyacrylic acid (CeO2@PAA) and positively charged poly (2-(methacryloyloxy)ethyl-trimethyl-ammonium chloride (CeO2@PMETAC), could induce systemic toxicity. As CeO2 has limited colloidal stability, which might result in vascular occlusion, intraperitoneal injection was used instead of intravenous administration. C57Bl/6 mice were four times injected with three different doses of each nanoceria-based sample (corresponding to 1.8, 5.3 and 16 mg Ce/kg BW/administration) for a total period of 14 days. CeO2@PMETAC induced a significant dose-dependent neutrophilia. Histopathological evaluation showed inflammatory processes in the capsule of liver, kidney, and spleen of animals at all doses of CeO2@PMETAC, and with the highest dose of CeO2@PAA and CeO2. However, none of the nanoceria-based samples tested increased the level of DNA damage or micronuclei in blood cells, even though Ce was detected by inductively coupled plasma mass spectrometry analyses in the bone marrow. Only CeO2@PMETAC induced the presence of megakaryocytes in the spleen. A higher accumulation of Ce in mononuclear phagocyte system organs (liver, spleen and bone marrow) was observed after CeO2@PMETAC treatment compared with CeO2@PAA and CeO2.

Miconazole loaded chitosan-based nanoparticles for local treatment of vulvovaginal candidiasis fungal infections.

OBJECTIVES: In this study, polymeric nanoparticles based on chitosan incorporating the antifungal miconazole nitrate were fabricated and testedin vivo using murine vulvovaginal candidiasis. METHODS: Nanoparticles prepared by the ionotropic gelation method presented 200 to 300 nm diameter and polydispersity indexes ranging from 0.2 to 0.4. The nanoparticles were prepared to incorporate 63.9 mg/mL of miconazole nitrate to be testedin vivo. Murine vulvovaginal candidiasis was standardized using estradiol valerate before the animals were challenged by Candida albicans. RESULTS: The treatment using chitosan nanoparticles within miconazole nitrate presented the same therapeutic efficacy as miconazole nitrate in a commercial cream formulation, however using the antifungal content about seven-fold lower. This increase in the miconazole nitrate's therapeutic efficacy is may be due to the down-regulation of interleukin 10 (IL-10) expression. CONCLUSIONS: Our data represent a proof of concept that can be exploited to achieve an alternative and promising therapy for the treatment of vulvovaginal candidiasis.

Magneto low-density nanoemulsion (MLDE): A potential vehicle for combined hyperthermia and photodynamic therapy to treat cancer selectively.

In this paper, we introduce a new drug delivery system (DDS) called magneto low-density nanoemulsion (MLDE), which can carry maghemite nanoparticles and Chlorin e6 as an active photosensitizer drug. This design can enhance tumor damage after minor heat dissipation and/or minimum visible light photosensitization doses by classical magnetic hyperthermia (MHT) and photodynamic therapy (PDT), respectively. We establish protocols to prepare the MLDE and to load the drug combination onto it. The MLDE prepared herein is nanometric (<200 nm), has high encapsulation efficiency, and is stable for at least 12 months in water dispersions. Flow cytometry results demonstrated that MLDE presents targeted selectivity toward the MCF-7 breast cancer cell line but not in NHI-3T3 mouse fibroblast cell lines, because the MCF-7 cancer cell surface contains overexpressed low density lipoprotein (LDL) receptors. Despite this targeted effect, MHT or PDT alone does not prompt significant antiproliferative outcomes. On the other hand, MHT and PDT in combination induce a strong and synergic action on MCF-7 cells and reduce the cell viability. In conclusion, the developed MLDE deserves further investigation because it is biocompatible, displays good encapsulation efficiency, and is highly stable. Moreover, it is selectively taken up by cancer cell surfaces with receptor recognition based on LDL receptor overexpression, which potentiates the action of combined MHT and PDT.

Decoration of a Poly(methyl vinyl ether-co-maleic anhydride)-Shelled Selol Nanocapsule with Folic Acid Increases Its Activity Against Different Cancer Cell Lines In Vitro.

Due to the low therapeutic index of different chemotherapeutic drugs used for cancer treatment, the development of new anticancer drugs remains an intense field of research. A recently developed mixture of selenitetriacylglycerides, selol, was shown to be active against different cancer cells in vitro. As this compound is highly hydrophobic, it was encapsulated, in a previous study, into poly(methyl vinyl ether-co-maleic anhydride)-shelled nanocapsules in order to improve its dispersibility in aqueous media. Following this line of research, the present report aimed at enhancing the In Vitro activity of the selol nanocapsules against cancerous cells by decorating their surface with folic acid. It is known that several cancer cells overexpress folate receptors. Stable folic acid-decorated selol nanocapsules (SNP-FA) were obtained, which showed to be spherical, with a hydro-dynamic diameter of 364 nm, and zeta potential of -24 mV. In comparison to non-decorated selol nanocapsules, SNP-FA presented higher activity against 4T1, MCF-7 and HeLa cells. Moreover, the decoration of the nanocapsules did not alter their toxicity towards fibroblasts, NIH-3T3 cells. These results show that the decoration with folic acid increased the toxicity of selol nanocapsules to cancer cells. These nanocapsules, besides enabling to disperse selol in an aqueous medium, increased the toxicity of this drug In Vitro, and may be useful to treat cancer in vivo, potentially increasing the specificity of selol towards cancer cells.

Selol nanocapsules with a poly(methyl vinyl ether-co-maleic anhydride) shell conjugated to doxorubicin for combinatorial chemotherapy against murine breast adenocarcinoma in vivo.

Nanocapsules containing selol and doxorubicin (NCS-DOX) with an oily core of selol and a shell of poly(methyl vinyl ether-co-maleic anhydride) covalently conjugated to doxorubicin were developed in a previous work. In this study, these nanocapsules showed a similar antitumour effect in comparison to the free doxorubicin (DOX) treatment, but showed no evident DOX-related cardiotoxicity, as evidenced by serum creatine kinase-MB (CK-MB) activity. The histopathological analysis showed that the free DOX treatment induced more intense morphological damage to myocardial tissues in comparison to NCS-DOX treatment. Animals treated with free DOX presented important muscle fibre degradation and animals treated with NCS-DOX, heart tissue did not present signals of muscle fibre degeneration. These results indicate that the cardiotoxicity related to DOX is reduced when this drug is carried by the NCS-DOX. Noteworthy, biodistribution analyses showed that NCS-DOX accumulated more intensely in tumours than the free DOX. Thus, this study reinforces the importance of the development of nanocapsules as drug carriers for the treatment of cancer.

Nanocapsules for the co-delivery of selol and doxorubicin to breast adenocarcinoma 4T1 cells in vitro.

Nanocapsules (NCS-DOX) with an oily core of selol and a shell of poly(methyl vinyl ether-co-maleic anhydride) covalently conjugated to doxorubicin were developed. These nanocapsules are spherical, with an average hydrodynamic diameter of about 170 nm, and with negative zeta potential. NCS-DOX effectively co-delivered the selol and the doxorubicin into 4T1 cells and changed the intracellular distribution of DOX from the nuclei to the mitochondria. Moreover, a significantly increased cytotoxicity against 4T1 cells was observed, which is suggestive of additive or synergic effect of selol and doxorubicin. In conclusion, PVM/MA nanocapsules are suitable platforms to co-deliver drugs into cancer cells.

Lipid nanoemulsion passive tumor accumulation dependence on tumor stage and anatomical location: a new mathematical model for in vivo imaging biodistribution studies.

Nanoparticle delivery to tumor tissue is one of the most important applications of nanomedicine. However, the literature shows that this pharmacological event is highly-affected by several tumor biology characteristics, including tumor size and maturation. Thus, the objective of the present study is to report on the investigation of the biodistribution of a lipid nanoemulsion (NE) in a breast cancer tumor model using in vivo imaging techniques. As highlights of this study, we can indicate that the biodistribution was measured in different tumor sites (primary and metastatic tumors) and in the same experimental mice for four subsequent weeks. With this approach it is possible to observe that the NE tumor delivery is significantly altered during tumor growth and metastasis progression. Furthermore, in the present report we introduce a phenomenological mathematical model that successfully explains the delivery behavior of a hydrophobic infrared fluorescent NE marker to both primary tumor and metastatic lesions. We believe that these data, in addition to the phenomenological mathematical model, are relevant to understanding how the stage of tumor development can alter macromolecule and/or nanoparticle delivery to tumor tissues, thus improving the efficacy of the passive delivery features promoted by tumor biology.

Cu2+-Complex of hydrophilic nitrogen-rich polymer dots applied as a new MRI contrast agent.

We report on a novel Cu2+-complex of nitrogen-rich polymer dots for magnetic resonance imaging (MRI). The N-rich polymer dots are prepared from N-vinyl imidazole (VIm) by a one-pot hydrothermal synthesis at 220 °C (24 h) and used later on to fabricate a Cu2+-PVIm dot complex via efficient incorporation of Cu2+ into aqueous medium. The obtained Cu2+-PVIm dot complexes display relaxivity (r1 = 1.05 mM-1 s-1) two times higher than Cu2+ in aqueous solution (r1 = 0.43 mM-1 s-1) and three times higher than Cu2+ in aqueous solution coordinated with VIm monomers (r1 = 0.32 mM-1 s-1), which show a remarkable contrast enhancement for T1-weighted MRI while efficiently labeling MCF-7 cells and other biomedical applications.

Magnetic nanohydrogel obtained by miniemulsion polymerization of poly(acrylic acid) grafted onto derivatized dextran.

This study describes the synthesis of magnetic nanohydrogels by miniemulsion polymerization technique. Dextran was derivatized by the glycidyl methacrylate to anchor vinyl groups on polysaccharides backbone, allowing its use as a macromonomer for miniemulsion polymerization, as confirmed by proton nuclear magnetic resonance spectroscopy (13C NMR). Magnetite nanoparticles were synthesized by coprecipitation, followed by air oxidation to maghemite. The results of X-ray diffractometry (XRD), Raman and transmission electron microscopy (TEM) analysis showed that maghemite nanoparticles were obtained with a diameter of 5.27nm. The entrapment of iron oxide nanoparticles in a dextran nanohydrogel matrix was confirmed by thermogravimetric analysis (TGA), scanning transmission electron microscopy (STEM) and Zeta potential data. The magnetic nanohydrogels presented superparamagnetic behavior and were colloidal stable in physiological during 30days. Our findings suggest that the synthesized magnetic nanohydrogel are potential candidates for use in drug delivery systems due to its physicochemical and magnetic properties.

Antifungal Activity of Amphotericin B Conjugated to Nanosized Magnetite in the Treatment of Paracoccidioidomycosis.

This study reports on in vitro and in vivo tests that sought to assess the antifungal activity of a newly developed magnetic carrier system comprising amphotericin B loaded onto the surface of pre-coated (with a double-layer of lauric acid) magnetite nanoparticles. The in vitro tests compared two drugs; i.e., this newly developed form and free amphotericin B. We found that this nanocomplex exhibited antifungal activity without cytotoxicity to human urinary cells and with low cytotoxicity to peritoneal macrophages. We also evaluated the efficacy of the nanocomplex in experimental paracoccidioidomycosis. BALB/c mice were intratracheally infected with Paracoccidioides brasiliensis and treated with the compound for 30 or 60 days beginning the day after infection. The newly developed amphotericin B coupled with magnetic nanoparticles was effective against experimental paracoccidioidomycosis, and it did not induce clinical, biochemical or histopathological alterations. The nanocomplex also did not induce genotoxic effects in bone marrow cells. Therefore, it is reasonable to believe that amphotericin B coupled to magnetic nanoparticles and stabilized with bilayer lauric acid is a promising nanotool for the treatment of the experimental paracoccidioidomycosis because it exhibited antifungal activity that was similar to that of free amphotericin B, did not induce adverse effects in therapeutic doses and allowed for a reduction in the number of applications.

Magnetic nanoparticle film reconstruction modulated by immersion within DMSA aqueous solution.

The process of reconstruction of pre-fabricated films comprising maghemite nanoparticles deposited onto flat glass substrates triggered by immersion into aqueous solutions of meso-2,3-dimercaptosuccinic acid (DMSA) at increasing concentration (0.025, 0.050, and 0.100 mol/L) is herein reported. The evolution of this process was assessed by measuring the time (t) dependence of the particle analysis histogram width (W) extracted from atomic force microscopy images. Furthermore, a physical picture to model the film reconstruction which provides reconstruction time constants associated to single particles (τ1) and small agglomerates (τn), the key units associated to the process, ranging from τ1 = 2.9 and τn = 3.4 hour (0.025 mol/L) to τ1 = 5.1 and τn = 4.6 hour (0.100 mol/L) is proposed. The nanoparticle-based film reconstruction triggered by an exogenous stimulus, the use of the W versus t data to describe the process and the model picture accounting for the recorded data have not been previously reported.