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Iron Oxide Nanoparticles (IONPs) hold the potential to exert significant influence on fighting cancer through their theranostics capabilities as contrast agents (CAs) for magnetic resonance imaging (MRI) and as mediators for magnetic hyperthermia (MH). In addition, these capabilities can be improved by doping IONPs with other elements. In this work, the synthesis and characterization of single-core and alloy ZnFe novel magnetic nanoparticles (MNPs), with improved magnetic properties and more efficient magnetic-to-heat conversion, are reported. Remarkably, the results challenge classical nucleation and growth theories, which cannot fully predict the final size/shape of these nanoparticles and, consequently, their magnetic properties, implying the need for further studies to better understand the nanomagnetism phenomenon. On the other hand, leveraging the enhanced properties of these new NPs, successful tumor therapy by MH is achieved following their intravenous administration and tumor accumulation via the enhanced permeability and retention (EPR) effect. Notably, these results are obtained using a single low dose of MNPs and a single exposure to clinically suitable alternating magnetic fields (AMF). Therefore, as far as the authors are aware, for the first time, the successful application of intravenously administered MNPs for MRI-tracked MH tumor therapy in passively targeted tumor xenografts using clinically suitable conditions is demonstrated.

Bimodal medical imaging based on magnetic resonance imaging (MRI) and computed tomography (CT) is a well-known strategy to increase the diagnostic accuracy. The most recent advances in MRI and CT instrumentation are related to the use of ultra-high magnetic fields (UHF-MRI) and different working voltages (spectral CT), respectively. Such advances require the parallel development of bimodal contrast agents (CAs) that are efficient under new instrumental conditions. In this work, we have synthesized, through a precipitation reaction from a glycerol solution of the precursors, uniform barium dysprosium fluoride nanospheres with a cubic fluorite structure, whose size was found to depend on the Ba/(Ba + Dy) ratio of the starting solution. Moreover, irrespective of the starting Ba/(Ba + Dy) ratio, the experimental Ba/(Ba + Dy) values were always lower than those used in the starting solutions. This result was assigned to lower precipitation kinetics of barium fluoride compared to dysprosium fluoride, as inferred from the detailed analysis of the effect of reaction time on the chemical composition of the precipitates. A sample composed of 34 nm nanospheres with a Ba0.51Dy0.49F2.49 stoichiometry showed a transversal relaxivity (r2) value of 147.11 mM-1·s-1 at 9.4 T and gave a high negative contrast in the phantom image. Likewise, it produced high X-ray attenuation in a large range of working voltages (from 80 to 140 kVp), which can be attributed to the presence of different K-edge values and high Z elements (Ba and Dy) in the nanospheres. Finally, these nanospheres showed negligible cytotoxicity for different biocompatibility tests. Taken together, these results show that the reported nanoparticles are excellent candidates for UHF-MRI/spectral CT bimodal imaging CAs.

Nanomedicine has been long hailed as a game changer for treating several ailments, but its translation from bench to bedside is facing some hurdles. Over the past few decades, there have been a plethora of reports regarding the synthesis of nanomaterials and, in particular, of iron oxide nanoparticles. However, very few reports discuss the role of stirring speed, reproducibility, and scalability. This work attempts to comprehensively revisit the most widely used existing protocols and discuss how the particle size or shape varies when certain parameters are altered and different precursors and solvents are used. It also discusses the probability of reproducing and scaling up the reactions while deciphering the effect of the ramp rate on size and shape. Lastly, it upgrades the existing methods and suggests a modification to produce highly reproducible and scalable nanoparticles of ∼4 nm, which can be further tuned to ∼2 nm by merely modifying the stirring speed.

The progressive forms of multiple sclerosis (MS) primary progressive MS (PPMS) and secondary progressive MS (SPMS) are clinically distinguished by the rate at which symptoms worsen. Little is however known about the pathological mechanisms underlying the differential rate of accumulation of pathological changes. In this study, H NMR spectroscopy was used to measure low-molecular-weight metabolites in paired cerebrospinal fluid (CSF) and serum of PPMS, SPMS, and control patients, as well as to determine lipoproteins and glycoproteins in serum samples. Additionally, neurodegenerative and inflammatory markers, neurofilament light (NFL) and chitinase-3-like protein 1 (CHI3L1), and the concentration of seven metal elements, Mg, Mn, Cu, Fe, Pb, Zn, and Ca, were also determined in both CSF and serum. The results indicate that the pathological changes associated with progressive MS are mainly localized in the central nervous system (CNS). More so, PPMS and SPMS patients with comparable disability status are pathologically similar in relation to neurodegeneration, neuroinflammation, and some metabolites that distinguish them from controls. However, the rapid progression of PPMS from the onset may be driven by a combination of neurotoxicity induced by heavy metals coupled with diminished CNS antioxidative capacity associated with differential intrathecal ascorbate retention and imbalance of Mg and Cu.

In this study, we report the synthesis of gold-coated iron oxide nanoparticles capped with polyvinylpyrrolidone (Fe@Au NPs). The as-synthesized nanoparticles (NPs) exhibited good stability in aqueous media and excellent features as contrast agents (CA) for both magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Additionally, due to the presence of the local surface plasmon resonances of gold, the NPs showed exploitable “light-to-heat” conversion ability in the near-infrared (NIR) region, a key attribute for effective photothermal therapies (PTT). In vitro experiments revealed biocompatibility as well as excellent efficiency in killing glioblastoma cells via PTT. The in vivo nontoxicity of the NPs was demonstrated using zebrafish embryos as an intermediate step between cells and rodent models. To warrant that an effective therapeutic dose was achieved inside the tumor, both intratumoral and intravenous routes were screened in rodent models by MRI and CT. The pharmacokinetics and biodistribution confirmed the multimodal imaging CA capabilities of the Fe@AuNPs and revealed constraints of the intravenous route for tumor targeting, dictating intratumoral administration for therapeutic applications. Finally, Fe@Au NPs were successfully used for an in vivo proof of concept of imaging-guided focused PTT against glioblastoma multiforme in a mouse model.

La nanotecnología aporta interesantes herramientas para solventar algunos de los principales problemas relacionados con el diagnóstico y tratamiento convencional del cáncer, ej. baja sensibilidad de las técnicas de diagnostico por imagen, obtención de concentraciones subterapéuticas en el tumor. Además, estrategias de diseño avanzado han permitido la formulación de nanoestructuras con actividades adicionales frente al cáncer, ej. hipertermia antitumoral. Este trabajo pretende el diseño de nanopartículas (NPs) híbridas magnéticas que aúnen capacidades para el diagnóstico del cáncer mediante resonancia magnética de imagen (RMI) y para la hipertermia antitumoral.

La lucha frente al cáncer requiere de Medicina de precisión. En este sentido, la inclusión de nanopartículas (NPs) de óxido de hierro (ej. Fe3O4) en nanoplataformas poliméricas presenta gran interés por su potencial para constituir herramientas teranósticas [1]. En esta investigación se diseña y caracteriza un nanosistema multifuncional constituido por NPs de Fe3O4 embebidas en una nanomatriz de policaprolatona (PCL) funcionalizada con quitosano (CS). Se estudiará su capacidad como agentes de hipertermia, como sistemas de liberación ante estímulos de pH y temperatura de gemcitabina (GEM) y como agentes de contraste en RMI. Por último, se determinará su perfil de biodistribución.

Diagnostic imaging strongly relies on the use of contrast agents (CAs). In general terms, current CAs present undesirable side effects that encourage researchers and pharmaceutical companies to continually search for safer and more versatile alternatives. Here, we describe the synthesis and characterization of terbium-based nanorods (TbNRs) as a potential alternative to traditional CAs for magnetic resonance imaging (MRI) and X-ray computed tomography (CT). The paramagnetism and high atomic number of Tb provide TbNRs with both magnetic relaxivity and X-ray attenuation capabilities. After surface functionalization with a polyethylene glycol (PEG)-derived ligand, TbNRs showed high colloidal stability in physiological media. Additionally, toxicity studies conducted in cell cultures and zebrafish embryos demonstrated the safety of the as-synthesized TbNRs, thus supporting their potential use as CAs. Lastly, in vivo imaging experiments in mice demonstrated that TbNRs produce remarkable contrast enhancement on both MRI and CT.

Diagnostic imaging strongly relies on the use of contrast agents (CAs). In general terms, current CAs present undesirable side effects that encourage researchers and pharmaceutical companies to continually search for safer and more versatile alternatives. Here, we describe the synthesis and characterization of terbium-based nanorods (TbNRs) as a potential alternative to traditional CAs for magnetic resonance imaging (MRI) and X-ray computed tomography (CT). The paramagnetism and high atomic number of Tb provide TbNRs with both magnetic relaxivity and X-ray attenuation capabilities. After surface functionalization with a polyethylene glycol (PEG)-derived ligand, TbNRs showed high colloidal stability in physiological media. Additionally, toxicity studies conducted in cell cultures and zebrafish embryos demonstrated the safety of the as-synthesized TbNRs, thus supporting their potential use as CAs. Lastly, in vivo imaging experiments in mice demonstrated that TbNRs produce remarkable contrast enhancement on both MRI and CT.

In this study, we report the synthesis of gold-coated iron oxide nanoparticles capped with polyvinylpyrrolidone (Fe@Au NPs). The as-synthesized nanoparticles (NPs) exhibited good stability in aqueous media and excellent features as contrast agents (CA) for both magnetic resonance imaging (MRI) and X-ray computed tomography (CT). Additionally, due to the presence of the local surface plasmon resonances of gold, the NPs showed exploitable “light-to-heat” conversion ability in the near-infrared (NIR) region, a key attribute for effective photothermal therapies (PTT). In vitro experiments revealed biocompatibility as well as excellent efficiency in killing glioblastoma cells via PTT. The in vivo nontoxicity of the NPs was demonstrated using zebrafish embryos as an intermediate step between cells and rodent models. To warrant that an effective therapeutic dose was achieved inside the tumor, both intratumoral and intravenous routes were screened in rodent models by MRI and CT. The pharmacokinetics and biodistribution confirmed the multimodal imaging CA capabilities of the Fe@AuNPs and revealed constraints of the intravenous route for tumor targeting, dictating intratumoral administration for therapeutic applications. Finally, Fe@Au NPs were successfully used for an in vivo proof of concept of imaging-guided focused PTT against glioblastoma multiforme in a mouse model.

Passive tumor targeting via the enhanced permeability and retention (EPR) effect has long been considered the most effective mechanism for the accumulation of nanoparticles inside solid tumors. However, several studies have demonstrated that the EPR effect is largely dependent on the tumor type and location. Particularly complex is the situation in brain tumors, where the presence of the blood–brain tumor barrier (BBTB) adds an extra limiting factor in reaching the tumor interstitium. However, it remains unclear whether these restraints imposed by the BBTB prevent the EPR effect from acting as an efficient tumor targeting mechanism for metallic nanoparticles. In this work, we have studied the EPR effect of metallic magnetic nanoparticles (MMNPs) in a glioblastoma (GBM) model by parametric MRI. Our results showed that only MMNPs ≤50 nm could reach the tumor interstitium, whereas larger MMNPs were unable to cross the BBTB. Furthermore, even for MMNPs around 30–50 nm, the amount of them found within the tumor was scarce and restricted to the vicinity of large tumor vessels, indicating that the BBTB strongly limits the passive accumulation of metallic nanoparticles in brain tumors. Therefore, active targeting becomes the most reasonable strategy to target metallic nanoparticles to GBMs.

BACKGROUND: In obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model. METHODS: BM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using 1H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay. RESULTS: Four days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC sho

In this work, we report the synthesis and characterization of three magnetic nanosystems, CoFe2O4, CoFe2O4@ZnFe2O4, and CoFe2O4@MnFe2O4, which were developed as potential theranostic agents for magnetic hyperthermia and magnetic resonance imaging (MRI). These nanosystems have been thoroughly characterized by X-ray Diffraction (XRD), Transmission Electron Miscroscopy (TEM), Dark Field-TEM (DF-TEM), Vibrating Sample Magnetometry (VSM), and inductive heating, in order to elucidate their structure, morphology, and magnetic properties. The bi-magnetic CoFe2O4@ZnFe2O4 and CoFe2O4@MnFe2O4 nanoparticles (NPs) exhibited a core-shell structure with a mean average particle size of 11.2 ± 1.4 nm and 14.4 ± 2.4 nm, respectively. The CoFe2O4@MnFe2O4 NPs showed the highest specific absorption rate (SAR) values (210-320 W/g) upon exposure to an external magnetic field, along with the highest saturation magnetization (Ms). Therefore, they were selected for functionalization with the PEGylated ligand to make them stable in aqueous media. After the functionalization process, the NPs showed high magnetic relaxivity values and very low cytotoxicity, demonstrating that CoFe2O4@MnFe2O4 is a good candidate for in vivo applications. Finally, in vivo MRI experiments showed that PEGylated CoFe2O4@MnFe2O4 NPs produce high T2 contrast and exhibit very good stealth properties, leading to the efficient evasion of the mononuclear phagocyte system. Thus, these bi-magnetic core-shell NPs show great potential as theranostic agents for in vivo applications, combining magnetic hyperthermia capabilities with high MRI contrast.

Iron oxide nanoparticles (IONPs) have emerged as a promising alternative to conventional contrast agents (CAs) for magnetic resonance imaging (MRI). They have been extensively investigated as CAs due to their high biocompatibility and excellent magnetic properties. Furthermore, the ease of functionalization of their surfaces with different types of ligands (antibodies, peptides, sugars, etc.) opens up the possibility of carrying out molecular MRI. Thus, IONPs functionalized with epithelial growth factor receptor antibodies, short peptides, like RGD, or aptamers, among others, have been proposed for the diagnosis of various types of cancer, including breast, stomach, colon, kidney, liver or brain cancer. In addition to cancer diagnosis, different types of IONPs have been developed for other applications, such as the detection of brain inflammation or the early diagnosis of thrombosis. This review addresses key aspects in the development of IONPs for MRI applications, namely, synthesis of the inorganic core, functionalization processes to make IONPs biocompatible and also to target them to specific tissues or cells, and finally in vivo studies in animal models, with special emphasis on tumor models.

Clickable magnetic nanoparticles have attracted great attention as potential nanoplatforms for biomedical applications because of the high functionalization efficiency of their surfaces with biomolecules, which facilitates their bio-compatibilization. However, the design and synthesis of clickable NPs is still challenging because of the complexity of the chemistry on the magnetic NP surface, thus robust methods that improve the ligand synthesis and the transfer of magnetic NPs in physiological media being in high-demand. In this work, we developed a versatile and enhanced synthetic route to fabricate potentially clickable IONPs of interest in nanomedicine. Catechol anchor ligands with different stereoelectronic features were synthetized from a hetero bi-functional PEG spacer backbone. The resulting catechol ligands transferred in good yields and high stability to magnetic NPs by an improved energetic ligand exchange method that combines sonication and high temperature. The azido functionalized IONPs exhibited excellent characteristics as T2 MRI contrast agents with low cytotoxicity, making these clickable magnetic NPs promising precursors for nanomedicines.

Progress in the field of biocompatible SERS nanoparticles has promising prospects for biomedical applications. In this work, we have developed a biocompatible Raman probe by combining anisotropic silver nanoparticles with the dye rhodamine 6G followed by subsequent coating with bovine serum albumin. This nanosystem presents strong SERS capabilities in the near infrared (NIR) with a very high (2.7 × 107) analytical enhancement factor. Theoretical calculations reveal the effects of the electromagnetic and chemical mechanisms in the observed SERS effect for this nanosystem. Finite element method (FEM) calculations showed a considerable near field enhancement in NIR. Using density functional quantum chemical calculations, the chemical enhancement mechanism of rhodamine 6G by interaction with the nanoparticles was probed, allowing us to calculate spectra that closely reproduce the experimental results. The nanosystem was tested in cell culture experiments, showing cell internalization and also proving to be completely biocompatible, as no cell death was observed. Using a NIR laser, SERS signals could be detected even from inside cells, proving the applicability of this nanosystem as a biocompatible SERS probe.

Objective. To investigate if histogram analysis and visually assessed heterogeneity of diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping can predict molecular subtypes of invasive breast cancers. Materials and Methods. In this retrospective study, 91 patients with invasive breast carcinoma who underwent preoperative magnetic resonance imaging (MRI) with DWI at our institution were included. Two radiologists delineated a 2-D region of interest (ROI) on ADC maps in consensus. Tumors were also independently classified into low and high heterogeneity based on visual assessment of DWI. First-order statistics extracted through histogram analysis within the ROI of the ADC maps (mean, 10th percentile, 50th percentile, 90th percentile, standard deviation, kurtosis, and skewness) and visually assessed heterogeneity were evaluated for associations with tumor receptor status (ER, PR, and HER2 status) as well as molecular subtype. esults. HER2-positive lesions demonstrated significantly higher mean (), Perc50 (), and Perc90 (), with AUCs of 0.605, 0.592, and 0.652, respectively, than HER2-negative lesions. No significant differences were found in the histogram values for ER and PR statuses. Neither quantitative histogram analysis based on ADC maps nor qualitative visual heterogeneity assessment of DWI images was able to significantly differentiate between molecular subtypes, i.e., luminal A versus all other subtypes (luminal B, HER2-enriched, and triple negative) combined, luminal A and B combined versus HER2-enriched and triple negative combined, and triple negative versus all other types combined. Conclusion. Histogram analysis and visual heterogeneity assessment cannot be used to differentiate molecular subtypes of invasive breast cancer.