Atomic Basal Defect-Rich MoS2 by One-Step Synthesis and Mechanism Exploration.

Two-dimensional molybdenum disulfide (2D MoS2) shows great promise as a surface-enhanced Raman scattering (SERS) substrate due to its strong exciton resonance. However, the inert basal plane limits the performance of SERS. In this work, a strategy is proposed for the one-step synthesis of atomically basal defect-rich MoS2. The study first reveals that NaCl plays a two-stage role in the growth process, where NaCl initially promotes the rapid growth of large MoS2 as previously reported, and then promotes the formation of atomic basal defects dominated by single sulfur vacancies. Additionally, spectral changes induced by modulation of experimental parameters and density function theory calculation show that defect generation occurs during cooling. Meanwhile, the ratio of E 2 g 1 ${\mathrm{E}}_{{\mathrm{2g}}}^{\mathrm{1}}$ to A1g in defect-rich MoS2 exhibits different variation trends compared with pristine MoS2 in power-dependent Raman, and the ratio increases with increasing basal defects. In SERS tests, the limit of detection for rhodamine 6G reached 10-9 m, which is comparable to the performance of conventional noble metal SERS substrate. The activation strategy of the inert basal plane is applicable to other 2D transition metal dichalcogenides, and further has the potential to enhance performance in other domains, such as SERS and hydrogen evolution reactions.

Bifunctional Hexadentate Pyclen-based Chelating Agent for Mild Radiofluorination in Aqueous Solution at Room Temperature with a Ga-18F Ternary Complex.

Positron Emission Tomography (PET) is used in oncology for tumor diagnosis, commonly relying on fluorine-18 (18F) emission detection. The conventional method of 18F incorporation on to probes by covalent bonding is harsh for sensitive biomolecules, which are nonetheless compounds of choice for the development of targeted probes. This study explores gallium-18F (Ga18F) coordination, a milder alternative method occurring in aqueous media at the final stage of radiosyntheses. Pyclen-based chelating agents were proposed to capture (GaF) species at room temperature and pH ≥ 5 making the radiofluorination process compatible with heat- and acid-sensitive biomolecules. Highly promising results were obtained with the PC2A-based chelating agent LH2 derived from the new bifunctional PC2A-OAE-NCS compound. The solid-state structure of GaF(L) was elucidated by X-ray diffraction and revealed an unconventional heptacoordination of Ga(III). A high radiochemical conversion (RCC) of 86% was achieved at room temperature, in water at pH 5 within 20 minutes. Stability studies showed the robustness of the GaF(L) complex in aqueous media for at least one day and at least one hour for the radiolabeled analog Ga18F(L). These findings demonstrated that PC2A-based compounds are chelating agents of choice for (Ga18F) species, suggesting a real technological breakthrough for PET imaging and precision medicine.

HPLC/ESI-MS Characterization of Phenolic Compounds from Cnicus benedictus L. Roots: A Study of Antioxidant, Antibacterial, Anti-Inflammatory, and Anti-Alzheimer's Activity.

The phenolic composition of Cnicus benedictus roots from four Algerian regions was investigated. Extractions were performed in both hydro-methanolic (30 : 70, v/v) and hydro-ethanolic (30 : 70, v/v) solvents. Their efficiency was determined in terms of the qualitative and quantitative composition in phenolic compounds by HPLC-LC/MS of the different extracts isolated from C. Benedictus roots. Cnicus benedictus roots extract have been characterized by high content of phenolic compounds, where the trans chalcone, 2,3-dihydro flavone, 3-hydroxy flavone and cinnamic acid constitute the major components, in addition to fourteen minor acidic compounds and flavonoids as rutin. The hydro-methanolic extract was the richest in phenolic compounds yield from C benedictus. On the other hand, hydro methanolic (30 : 70, v/v) and hydro ethanolic (30 : 70, v/v) extracts exhibited a high anti-inflammatory activity by in vitro 5-lipoxygenase inhibitory activity (IC50 : 6.05±94.16 µg/mL) as well as by in silico docking according two methods. Likewise, anti-Alzheimer activity of extracts was confirmed by this last technique taking into account the major compounds identified. Antibacterial tests revealed interesting results compared to amoxicillin for the different regions studied with a high content in trans chalcone and 3-hydroxy Flavone.

A Review on the Design of Carbon-Based Nanomaterials as MRI Contrast Agents.

The administration of magnetic resonance imaging (MRI) contrast agents (CAs) has been conducted since 1988 by clinicians to enhance the clarity and interpretability of MR images. CAs based on gadolinium chelates are the clinical standard used worldwide for the diagnosis of various pathologies, such as the detection of brain lesions, the visualization of blood vessels, and the assessment of soft tissue disorders. However, due to ongoing concerns associated with the safety of gadolinium-based contrast agents, considerable efforts have been directed towards developing contrast agents with better relaxivities, reduced toxicity, and eventually combined therapeutic modalities. In this context, grafting (or encapsulating) paramagnetic metals or chelates onto (within) carbon-based nanoparticles is a straightforward approach enabling the production of contrast agents with high relaxivities while providing extensive tuneability regarding the functionalization of the nanoparticles. Here, we provide an overview of the parameters defining the efficacy of lanthanide-based contrast agents and the subsequent developments in the field of nanoparticular-based contrast agents incorporating paramagnetic species.

A Nanoparticle Ink Allowing the High Precision Visualization of Tissue Engineered Scaffolds by MRI.

Hydrogels are widely used as cell scaffolds in several biomedical applications. Once implanted in vivo, cell scaffolds must often be visualized, and monitored overtime. However, cell scaffolds appear poorly contrasted in most biomedical imaging modalities such as magnetic resonance imaging (MRI). MRI is the imaging technique of choice for high-resolution visualization of low-density, water-rich tissues. Attempts to enhance hydrogel contrast in MRI are performed with "negative" contrast agents that produce several image artifacts impeding the delineation of the implant's contours. In this study, a magnetic ink based on ultra-small iron oxide nanoparticles (USPIONs; <5 nm diameter cores) is developed and integrated into biocompatible alginate hydrogel used in cell scaffolding applications. Relaxometric properties of the magnetic hydrogel are measured, as well as biocompatibility and MR-visibility (T1 -weighted mode; in vitro and in vivo). A 2-week MR follow-up study is performed in the mouse model, demonstrating no image artifacts, and the retention of "positive" contrast overtime, which allows very precise delineation of tissue grafts with MRI. Finally, a 3D-contouring procedure developed to facilitate graft delineation and geometrical conformity assessment is applied on an inverted template alginate pore network. This proof-of-concept establishes the possibility to reveal precisely engineered hydrogel structures using this USPIONs ink high-visibility approach.

New Biocompatible ß-Phosphorylated Linear Nitrones Targeting Mitochondria: Protective Effect in Apoptotic Cells.

The mitochondrion, an essential organelle involved in cellular respiration, energy production, and cell death, is the main cellular source of reactive oxygen species (ROS), including superoxide. Mitochondrial diseases resulting from uncontrolled/excess ROS generation are an emerging public health concern and there is current interest in specific mitochondriotropic probes to get information on in-situ ROS production. As such, nitrones vectorized by the triphenylphosphonium (TPP) cation have recently drawn attention despite reported cytotoxicity. Herein, we describe the synthesis of 13 low-toxic derivatives of N-benzylidene-1-diethoxyphosphoryl-1-methylethylamine N-oxide (PPN) alkyl chain-grafted to a pyridinium, triethylammonium or berberinium lipophilic cation. These nitrones showed in-vitro superoxide quenching activity and EPR/spin-trapping efficiency towards biologically relevant free radicals, including superoxide and hydroxyl radicals. Their mitochondrial penetration was confirmed by 31 P NMR spectroscopy, and their anti-apoptotic properties were assessed in Schwann cells treated with hydrogen peroxide. Two pyridinium-substituted PPNs were identified as potentially better alternatives to TPP nitrones conjugates for studying mitochondrial oxidative damage.

Nuclear magnetic resonance relaxometry to monitor chromium (VI) reduction by hydrogen peroxide, ascorbic acid, and aluminum powder.

The reduction of K2 Cr2 O7 solutions by H2 O2 was studied by nuclear magnetic resonance (NMR) relaxometry and UV-vis spectroscopy in HCl/KCl buffer (pH 2), NaCl/glycine/HCl buffer (pH 3), and sodium acetate/acetic acid buffer (pH 4). Because of Cr(III) paramagnetism, 1/T1 and 1/T2 of the solutions increase during the reduction of diamagnetic Cr(VI). This increase is proportional to the produced Cr(III) concentration. Using different initial H2 O2 concentrations, partially reduced Cr(VI) samples were prepared and studied by T1 and T2 relaxometry and by UV-vis spectroscopy. The correlation between the relaxation rates and the concentration of Cr(VI) remaining in the sample, measured by spectroscopy, was excellent. It was possible, thanks to the measurement of T2 , to study the kinetics of the reduction of K2 Cr2 O7 by H2 O2 in the pH 3 and pH 4 buffers. The reduction of Cr(VI) by ascorbic acid was successfully monitored by NMR relaxometry in the pH 2 buffer. The presence of complexing molecules/ions was shown to drastically influence the nuclear magnetic relaxation dispersion profiles of reduced K2 Cr2 O7 solutions: Both relaxation rates are divided by ~5 when citrate or acetate ions are present and by ~3 in the presence of ascorbic acid. Therefore, the comparison of relaxation results obtained in different reaction mixtures must be done carefully. When all the solutions are set to pH 0, which prevents any complexation, the longitudinal and transverse relaxation rates of all samples become comparable. Finally, as a proof of concept for a turbid solution, the kinetics of the reduction of a K2 Cr2 O7 solution by aluminum powder in the pH 2 buffer was successfully monitored.

Mn-Based MRI Contrast Agents: An Overview.

MRI contrast agents are required in the clinic to detect some pathologies, such as cancers. Nevertheless, at the moment, only small extracellular and non-specific gadolinium complexes are available for clinicians. Moreover, safety issues have recently emerged concerning the use of gadolinium complexes; hence, alternatives are urgently needed. Manganese-based MRI contrast agents could be one of these alternatives and increasing numbers of studies are available in the literature. This review aims at synthesizing all the research, from small Mn complexes to nanoparticular agents, including theranostic agents, to highlight all the efforts already made by the scientific community to obtain highly efficient agents but also evidence of the weaknesses of the developed systems.

In Vitro and In Silico Evaluation of Anticholinesterase and Antidiabetic Effects of Furanolabdanes and Other Constituents from Graptophyllum pictum (Linn.) Griffith.

Graptophyllum pictum is a tropical plant noticeable for its variegated leaves and exploited for various medicinal purposes. In this study, seven compounds, including three furanolabdane diterpenoids, i.e., Hypopurin E, Hypopurin A and Hypopurin B, as well as with Lupeol, ß-sitosterol 3-O-ß-d-glucopyranoside, stigmasterol 3-O-ß-d-glucopyranoside and a mixture of ß-sitosterol and stigmasterol, were isolated from G. pictum, and their structures were deduced from ESI-TOF-MS, HR-ESI-TOF-MS, 1D and 2D NMR experiments. The compounds were evaluated for their anticholinesterase activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BchE), as well as their antidiabetic potential through inhibition of α-glucosidase and α-amylase. For AChE inhibition, no sample had IC50 within tested concentrations, though the most potent was Hypopurin A, which had a percentage inhibition of 40.18 ± 0.75%, compared to 85.91 ± 0.58% for galantamine, at 100 µg/mL. BChE was more susceptible to the leaves extract (IC50 = 58.21 ± 0.65 µg/mL), stem extract (IC50 = 67.05 ± 0.82 µg/mL), Hypopurin A (IC50 = 58.00 ± 0.90 µg/mL), Hypopurin B (IC50 = 67.05 ± 0.92 µg/mL) and Hypopurin E (IC50 = 86.90 ± 0.76 µg/mL). In the antidiabetic assay, the furanolabdane diterpenoids, lupeol and the extracts had moderate to good activities. Against α-glucosidase, lupeol, Hypopurin E, Hypopurin A and Hypopurin B had appreciable activities but the leaves (IC50 = 48.90 ± 0.17 µg/mL) and stem (IC50 = 45.61 ± 0.56 µg/mL) extracts were more active than the pure compounds. In the α-amylase assay, stem extract (IC50 = 64.47 ± 0.78 µg/mL), Hypopurin A (IC50 = 60.68 ± 0.55 µg/mL) and Hypopurin B (IC50 = 69.51 ± 1.30 µg/mL) had moderate activities compared to the standard acarbose (IC50 = 32.25 ± 0.36 µg/mL). Molecular docking was performed to determine the binding modes and free binding energies of Hypopurin E, Hypopurin A and Hypopurin B in relation to the enzymes and decipher the structure-activity relationship. The results indicated that G. pictum and its compounds could, in general, be used in the development of therapies for Alzheimer's disease and diabetes.

In Vitro Evaluation of α-amylase and α-glucosidase Inhibition of 2,3-Epoxyprocyanidin C1 and Other Constituents from Pterocarpus erinaceus Poir.

Diabetes mellitus is a metabolic disorder which is one of the leading causes of mortality and morbidities in elderly humans. Chronic diabetes can lead to kidney failure, blindness, limb amputation, heart attack and stroke. Physical activity, healthy diets and medications can reduce the incidence of diabetes, so the search for more efficient antidiabetic therapies, most especially from natural products, is a necessity. Herein, extract from roots of the medicinal plant Pterocarpus erinaceus was purified by column chromatography and afforded ten compounds which were characterized by EIMS, HR-FAB-MS, 1D and 2D NMR techniques. Amongst them were, a new trimeric derivative of epicatechin, named 2,3-Epoxyprocyanidin C1 (1); two pentacyclic triterpenoids, friedelin (2) and betulin (3); angolensin (4); flavonoids such as 7-methoxygenistein (5), 7-methoxydaidzein (6), apigenin 7-O-glucoronide (8) and naringenin 7-O-ß-D-glucopyranoside (9); and an ellagic acid derivative (10). The extract and compounds were evaluated for their antidiabetic potential by α-amylase and α-glucosidase inhibitory assays. IC50 values of compound 7 (48.1 ± 0.9 µg/mL), compound 8 (48.6 ± 0.1 µg/mL), compound 9 (50.2 ± 0.5 µg/mL) and extract (40.5 ± 0.8 µg/mL) when compared to that of acarbose (26.4 ± 0.3 µg/mL) indicated good α-amylase inhibition. In the α-glucosidase assay, the extract (IC50 = 31.2 ± 0.1 µg/mL), compound 7 (IC50 = 39.5 ± 1.2 µg/mL), compound 8 (IC50 = 40.9 ± 1.3 µg/mL), compound 1 (IC50 = 41.6 ± 1.0 µg/mL), Compound 4 (IC50 = 43.4 ± 0.5 µg/mL), compound 5 (IC50 = 47.6 ± 0.9 µg/mL), compound 6 (IC50 = 46.3 ± 0.2 µg/mL), compound 7 (IC50 = 45.0 ± 0.8 µg/mL), compound 9 (IC50 = 44.8 ± 0.6 µg/mL) and compound 11 (IC50 = 47.5 ± 0.4 µg/mL) all had moderate-to-good inhibitions, compared to acarbose (IC50 = 22.0 ± 0.5 µg/mL). The ability to inhibit α-amylase and α-glucosidase indicates that P. erinaceus and its compounds can lower blood glucose levels by delaying hydrolysis of carbohydrates into sugars, thereby providing a source of natural antidiabetic remedy.

Novel Sterically Crowded and Conformationally Constrained α-Aminophosphonates with a Near-Neutral pKa as Highly Accurate 31P NMR pH Probes. Application to Subtle pH Gradients Determination in Dictyostelium discoideum Cells.

In order to discover new 31P NMR markers for probing subtle pH changes (<0.2 pH unit) in biological environments, fifteen new conformationally constrained or sterically hindered α-aminophosphonates derived from diethyl(2-methylpyrrolidin-2-yl)phosphonate were synthesized and tested for their pH reporting and cytotoxic properties in vitro. All compounds showed near-neutral pKas (ranging 6.28−6.97), chemical shifts not overlapping those of phosphorus metabolites, and spectroscopic sensitivities (i.e., chemical shifts variation Δδab between the acidic and basic forms) ranging from 9.2−10.7 ppm, being fourfold larger than conventional endogenous markers such as inorganic phosphate. X-ray crystallographic studies combined with predictive empirical relationships and ab initio calculations addressed the inductive and stereochemical effects of substituents linked to the protonated amine function. Satisfactory correlations were established between pKas and both the 2D structure and pyramidalization at phosphorus, showing that steric crowding around the phosphorus is crucial for modulating Δδab. Finally, the hit 31P NMR pH probe 1b bearing an unsubstituted 1,3,2-dioxaphosphorinane ring, which is moderately lipophilic, nontoxic on A549 and NHLF cells, and showing pKa = 6.45 with Δδab = 10.64 ppm, allowed the first clear-cut evidence of trans-sarcolemmal pH gradients in normoxic Dictyostelium discoideum cells with an accuracy of <0.05 pH units.

Myeloid tumor necrosis factor and heme oxygenase-1 regulate the progression of colorectal liver metastases during hepatic ischemia-reperfusion.

The liver ischemia-reperfusion (IR) injury that occurs consequently to hepatic resection performed in patients with metastases can lead to tumor relapse for not fully understood reasons. We assessed the effects of liver IR on tumor growth and the innate immune response in a mouse model of colorectal (CR) liver metastasis. Mice subjected to liver ischemia 2 days after intrasplenic injection of CR carcinoma cells displayed a higher metastatic load in the liver, correlating with Kupffer cells (KC) death through the activation of receptor-interating protein 3 kinase (RIPK3) and caspase-1 and a recruitment of monocytes. Interestingly, the immunoregulatory mediators, tumor necrosis factor-α (TNF-α) and heme oxygenase-1 (HO-1) were strongly upregulated in recruited monocytes and were also expressed in the surviving KC following IR. Using TNFflox/flox LysMcre/wt mice, we showed that TNF deficiency in macrophages and monocytes favors tumor progression after IR. The antitumor effect of myeloid cell-derived TNF involved direct tumor cell apoptosis and a reduced expression of immunosuppressive molecules such as transforming growth factor-ß, interleukin (IL)-10, inducible nitric oxyde synthase (iNOS), IL-33 and HO-1. Conversely, a monocyte/macrophage-specific deficiency in HO-1 (HO-1flox/flox LysMcre/wt ) or the blockade of HO-1 function led to the control of tumor progression post-liver IR. Importantly, host cell RIPK3 deficiency maintains the KC number upon IR, inhibits the IR-induced innate cell recruitment, increases the TNF level, decreases the HO-1 level and suppresses the tumor outgrowth. In conclusion, tumor recurrence in host undergoing liver IR is associated with the death of antitumoral KC and the recruitment of monocytes endowed with immunosuppressive properties. In both of which HO-1 inhibition would reinforce their antitumoral activity.

Mn2+ Complexes with Pyclen-Based Derivatives as Contrast Agents for Magnetic Resonance Imaging: Synthesis and Relaxometry Characterization.

Magnetic resonance imaging (MRI) has a leading place in medicine as an imaging tool of high resolution for anatomical studies and diagnosis of diseases, in particular for soft tissues that cannot be accessible by other modalities. Many research works are thus focused on improving the images obtained with MRI. This technique has indeed poor sensitivity, which can be compensated by using a contrast agent (CA). Today, the clinically approved CAs on market are solely based on gadolinium complexes that may induce nephrogenic systemic fibrosis for patients with kidney failure, whereas more recent studies on healthy rats also showed Gd retention in the brain. Consequently, researchers try to elaborate other types of safer MRI CAs like manganese-based complexes. In this context, the synthesis of Mn2+ complexes of four 12-membered pyridine-containing macrocyclic ligands based on the pyclen core was accomplished and described herein. Then, the properties of these Mn(II) complexes were studied by two relaxometric methods, 17O NMR spectroscopy and 1H NMR dispersion profiles. The time of residence (τM) and the number of water molecules (q) present in the inner sphere of coordination were determined by these two experiments. The efficacy of the pyclen-based Mn(II) complexes as MRI CAs was evaluated by proton relaxometry at a magnetic field intensity of 1.41 T near those of most medical MRI scanners (1.5 T). Both the 17O NMR and the nuclear magnetic relaxation dispersion profiles indicated that the four hexadentate ligands prepared herein left one vacant coordination site to accommodate one water molecule, rapidly exchanging, in around 6 ns. Furthermore, it has been shown that the presence of an additional amide bond formed when the paramagnetic complex is conjugated to a molecule of interest does not alter the inner sphere of coordination of Mn, which remains monohydrated. These complexes exhibit r1 relaxivities, large enough to be used as clinical MRI CAs (1.7-3.4 mM-1·s-1, at 1.41 T and 37 °C).

A new method of extracting polyphenols from honey using a biosorbent compared to the commercial resin amberlite XAD2.

A new extraction method of polyphenols from honey using a biodegradable resin was developed and compared with the common commercial resin amberlite XAD2. For this purpose, three honey samples of Algerian origin were selected for the different physicochemical and biochemical parameters study. After extraction of the target compounds by both resins, the polyphenol content was determined, the antioxidant activity was tested, and liquid chromatography-mass spectrometry analyses were performed for identification and quantification. The results showed that physicochemical and biochemical parameters meet the norms of the International Honey Commission, and the H1 sample seemed to be of high quality. The optimal conditions of extraction by biodegradable resin were a pH of 3, an adsorption dose of 40 g/L, a contact time of 50 min, an extraction temperature of 60°C, and no stirring. The regeneration and reuse number of both resins was three cycles. The polyphenol contents demonstrated a higher extraction efficiency of biosorbent than of XAD2, especially in H1. Liquid chromatography-mass spectrometry analyses allowed for the identification and quantification of 15 compounds in the different honey samples extracted using both resins and the most abundant compound was 3,4,5-trimethoxybenzoic acid. In addition, the biosorbent extracts showed stronger antioxidant activities than the XAD2 extracts.

Preliminary studies of 68Ga-NODA-USPION-BBN as a dual-modality contrast agent for use in positron emission tomography/magnetic resonance imaging.

The aim of this study was to propose a new dual-modality nanoprobe for positron emission tomography/magnetic resonance imaging (PET/MRI) for the early diagnosis of breast cancer. For synthesis of the nanoprobe, polyethylene glycol-coated ultra-small superparamagnetic iron-oxide nanoparticles (USPION) armed with NODA-GA chelate and grafted with bombesin (BBN) were radiolabeled with 68Ga. After characterization, in vitro studies to evaluate the cell binding affinity of the nanoprobe were done by performing Perl's Prussian blue cell staining and MRI imaging. Finally, for in vivo studies, magnetic resonance images were taken in SCID mice bearing breast cancer tumor pre- and post-injection, and a multimodal nanoScan PET/computed tomography was used to perform preclinical imaging of the radiolabeled nanoparticles. Afterwards, a biodistribution study was done on sacrificed mice. The results showed that the highest r1 and r2 values were measured for USPIONs at 20 and 60 MHz, respectively. From the in vitro studies, the optical density of the cells after incubation increased with the increase of the iron concentration and the duration of incubation. However, the T2 values decreased when the iron concentration increased. Furthermore, from in vivo studies, the T2 and signal intensity decreased during the elapsed time post-injection in the tumor area. In this study, the in vitro studies showed that the affinity of cancer cells to nanoprobe increases meaningfully after conjugation with BBN, and also by increasing the duration of incubation and the iron concentration. Meanwhile, the in vivo results confirmed that the blood clearance of the nanoprobe happened during the first 120 min post-injection of the radiolabeled nanoprobe and also confirmed the targeting ability of that to a gastrin-releasing peptide receptor positive tumor.

Combinatorial effects of radiofrequency hyperthermia and radiotherapy in the presence of magneto-plasmonic nanoparticles on MCF-7 breast cancer cells.

Here, the effects of combinatorial cancer therapy including radiotherapy (RT) and radiofrequency (RF) hyperthermia in the presence of gold-coated iron oxide nanoparticles (Au@IONPs), as a thermo-radio-sensitizer, are reported. The level of cell death and the ratio of Bax/Bcl2 genes, involved in the pathway of apoptosis, were measured to evaluate the synergistic effect of Au@IONPs-mediated RF hyperthermia and RT. MCF-7 human breast adenocarcinoma cells were treated with different concentrations of Au@IONPs. After incubation with NPs, the cells were exposed to RF waves (13.56 MHz; 100 W; 15 min). At the same time, thermometry was performed with an infrared (IR) camera. Then, the cells were exposed to 6 MV X-ray at various doses of 2 and 4 Gy. MTT (3-[4,5-dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide) assay was performed to evaluate cell viability and quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression ratio of Bax/Bcl2. Cellular uptake of nanoparticles was confirmed qualitatively and quantitatively. The results obtained from MTT assay and qRT-PCR studies showed that NPs and RF hyperthermia had no significant effect when applied separately, while their combination had synergistic effects on cell viability percentage and the level of apoptosis induction. A synergistic effect was also observed when the cancer cells were treated with a combination of NPs, RF hyperthermia, and RT. On the basis of the obtained results, it may be concluded that the use of magneto-plasmonic NPs in the process of hyperthermia and RT of cancer holds a great promise to develop a new combinatorial cancer therapy strategy.

Comparison of MRI Properties between Multimeric DOTAGA and DO3A Gadolinium-Dendron Conjugates.

The inherent lack of sensitivity of MRI needs the development of new Gd contrast agents in order to extend the application of this technique to cellular imaging. For this purpose, two multimeric MR contrast agents obtained by peptidic coupling between an amido amine dendron and GdDOTAGA chelates (premetalation strategy, G1-4GdDOTAGA) or DO3A derivatives which then were postmetalated (G1-4GdDO3A) have been prepared. By comparison to the monomers, an increase of longitudinal relaxivity has been observed for both structures. Especially for G1-4GdDO3A, a marked increase is observed between 20 and 60 MHz. This structure differs from G1-4GdDOTAGA by an increased rigidity due to the aromatic linker between each chelate and the organic framework. This has the effect of limiting local rotational movements, which has a positive impact on relaxivity.

Synthesis and Relaxometric Characterization of New Poly[N,N-bis(3-aminopropyl)glycine] (PAPGly) Dendrons Gd-Based Contrast Agents and Their in Vivo Study by Using the Dynamic Contrast-Enhanced MRI Technique at Low Field (1 T).

The synthesis of poly[N,N-bis(3-aminopropyl)glycine] (PAPGly) dendrons Gd-based contrast agents (GdCAs) via an orthogonal protection of the different functional groups and an activation/coupling strategy wherein a specific number of synthetic steps add a generation to the existing dendron has been described. The aim of this protocol is to build up two different generations of dendrons (G-0 or dendron's core, and G-1) with peripheral NH2 groups to conjugate a 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivative and afterwards to chelate with Gd3+ paramagnetic ions. These complexes, which have a well-defined molecular weight, are of relevance to MRI as an attempt to gain higher 1 H relaxivity by slowing down the rotation of molecule compared to monomeric Gd(III) complexes used as contrast agents and to increase the number of paramagnetic centers present in one molecular structure. From the study of their water 1 H longitudinal relaxation rate at different magnetic fields (NMRD, Nuclear Magnetic Relaxation Dispersion) and by evaluating the variable temperature 17 O-NMR data we determined the parameters characterizing the water exchange rate and the rotational correlation time of each complex, both affecting 1 H relaxivity. Furthermore, these two novel PAPGly GdCAs were objects of i) an in vivo study to determine their biodistributions in healthy C57 mice at several time points, and ii) the Dynamic Contrast-Enhanced MRI (DCE-MRI) approach to assess their contrast efficiency measured in the tumor region of C57BL/6 mice transplanted subcutaneously with B16-F10 melanoma cells. The aim of the comparison of these two dendrons GdCAs, having different molecular weights (MW), is to understand how MW and relaxivity may influence the contrast enhancement capabilities in vivo at low magnetic field (1 T). Significant contrast enhancement was observed in several organs (vessel, spleen and liver), already at 5 min post-injection, for the investigated CAs. Moreover, these CAs induced a marked contrast enhancement in the tumor region, thanks to the enhanced permeability retention effect of those macromolecular structures.

Silica Coated Iron/Iron Oxide Nanoparticles as a Nano-Platform for T2 Weighted Magnetic Resonance Imaging.

The growing concern over the toxicity of Gd-based contrast agents used in magnetic resonance imaging (MRI) motivates the search for less toxic and more effective alternatives. Among these alternatives, iron-iron oxide (Fe@FeOx) core-shell architectures have been long recognized as promising MRI contrast agents while limited information on their engineering is available. Here we report the synthesis of 10 nm large Fe@FeOx nanoparticles, their coating with a 11 nm thick layer of dense silica and functionalization by 5 kDa PEG chains to improve their biocompatibility. The nanomaterials obtained have been characterized by a set of complementary techniques such as infra-red and nuclear magnetic resonance spectroscopies, transmission electron microscopy, dynamic light scattering and zetametry, and magnetometry. They display hydrodynamic diameters in the 100 nm range, zetapotential values around -30 mV, and magnetization values higher than the reference contrast agent RESOVIST®. They display no cytotoxicity against 1BR3G and HCT116 cell lines and no hemolytic activity against human red blood cells. Their nuclear magnetic relaxation dispersion (NMRD) profiles are typical for nanomaterials of this size and magnetization. They display high r2 relaxivity values and low r1 leading to enhanced r2/r1 ratios in comparison with RESOVIST®. All these data make them promising contrast agents to detect early stage tumors.