For the development of redox responsive MRI probes based on the MnIII/MnII couple, stable complexation of both reduced and oxidized forms of the metal ion and appropriate tuning of the redox ...potential in the biologically relevant range are key elements. The water soluble fluorinated Mn-porphyrin derivative Mn-3 satisfies both requirements. In aqueous solutions, it can reversibly switch between MnIII/MnII oxidation states. In the presence of ascorbic acid or β-mercaptoethanol, the MnIII form undergoes reduction, which is slowly but fully reversed in the presence of air oxygen. A UV-Vis kinetic study of MnIII/MnII reduction under oxygen-free conditions yielded second-order rate constants, k2, of 46.1 M-1 s-1 and 13.8 M-1 s-1 for the reaction with ascorbic acid and β-mercaptoethanol, respectively. This could correspond, in the absence of oxygen, to a half-life of a few minutes in blood plasma and a few seconds in circulating immune cells where ascorbic acid reaches 20-40 μM and a few mM concentrations, respectively. In contrast to expectations based on the redox potential, reduction with glutathione or cysteine does not occur. It is prevented by the coordination of the glutathione carboxylate group(s) to MnIII in the axial position, as was evidenced by NMR data. Therefore, MnIII-3 acts as an ascorbate specific turn-on MRI probe, which in turn can be re-oxidized by oxygen. The relaxivity increase from the oxidized to the reduced form is considerably improved at medium frequencies (up to 80 MHz) with respect to the previously studied Mn-TPPS4 analogues; at 20 MHz, it amounts to 150%. No in vitro cytotoxicity is detectable for Mn-3 in the typical MRI concentration range. Finally, 19F NMR resonances of MnIII-3 are relatively sharp which could open further opportunities to exploit such complexes as paramagnetic 19F NMR probes.
Several studies have suggested the involvement of biogenic monoaminergic neurotransmission in bipolar disorder and in the therapy for this disease. In this study, the effects of the mood‐stabilizing ...drugs lithium, carbamazepine or valproate on the dopaminergic and adrenergic systems, particularly on D2‐like and β‐adrenergic receptors, were studied both in cultured rat cortical neurones and in rat prefrontal cortex. In vitro and in vivo data showed that stimulation of β‐adrenergic receptors with isoproterenol increased cyclic adenosine monophosphate (cAMP) levels and this effect was significantly inhibited by lithium, carbamazepine or valproate. The activation of dopamine D2‐like receptors with quinpirole decreased the isoproterenol‐induced rise in cAMP in control conditions. This inhibition was observed in vivo after chronic treatment of the rats with carbamazepine or valproate, but not after treatment with lithium or in cultured rat cortical neurones after 48 h exposure to the three mood stabilizers. Dopamine D2 and β1‐adrenergic receptors were found to be co‐localized in prefrontal cortical cells, as determined by immunohistochemistry, but western blot experiments revealed that receptor levels were differentially affected by treatment with the three mood stabilizers. These data show that mood stabilizers affect D2 receptor‐mediated regulation of β‐adrenergic signalling and that each drug acts by a unique mechanism.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Gold nanoparticles (AuNPs) are interesting for the design of new cancer theranostic tools, mainly due to their biocompatibility, easy molecular vectorization, and good biological half-life. Herein, ...we report a gold nanoparticle platform as a bimodal imaging probe, capable of coordinating Gd
for Magnetic Resonance Imaging (MRI) and
Ga
for Single Photon Emission Computed Tomography (SPECT) imaging. Our AuNPs carry a bombesin analogue with affinity towards the gastrin releasing peptide receptor (GRPr), overexpressed in a variety of human cancer cells, namely PC3 prostate cancer cells. The potential of these multimodal imaging nanoconstructs was thoroughly investigated by the assessment of their magnetic properties, in vitro cellular uptake, biodistribution, and radiosensitisation assays. The relaxometric properties predict a potential T
- and T
- MRI application. The promising in vitro cellular uptake of
Ga/Gd-based bombesin containing particles was confirmed through biodistribution studies in tumor bearing mice, indicating their integrity and ability to target the GRPr. Radiosensitization studies revealed the therapeutic potential of the nanoparticles. Moreover, the DOTA chelating unit moiety versatility gives a high theranostic potential through the coordination of other therapeutically interesting radiometals. Altogether, our nanoparticles are interesting nanomaterial for theranostic application and as bimodal T
- and T
- MRI / SPECT imaging probes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Mesoporous silica nanoparticles with a superparamagnetic iron oxide core were prepared in this work, in order to obtain multifunctional platforms with adequate features for cancer theranostics. Three ...different core-shell nanocomplexes were obtained: IO-OAm/mSiO2, IO-APTES/mSiO2 and IO/SiO2/mSiO2. In the case of IO-OAm/mSiO2 and IO-APTES/mSiO2, iron oxide (IO) was obtained by thermal decomposition, having in this case a coating of oleylamine (OAm) that was in the second formulation exchanged by (3-aminopropyl)triethoxysilane ligand (APTES). Regarding the IO/SiO2/mSiO2 formulation, iron oxide was synthesized by microemulsion. The mesoporous silica shell (mSiO2) on the IO nanoparticles was obtained by sol-gel and the final materials were dried by supercritical fluids drying. VSM confirmed the superparamagnetic behaviour of the nanoparticles, leading to MS of 4.0, 1.8 and 10.2 emu·g−1, for IO-OAm/mSiO2, IO-APTES/mSiO2 and IO/SiO2/mSiO2, respectively. NMR relaxometry has shown the potential of these nanoparticles to be used as T2 contrast agents, with r2 values as high as 63.93 s−1·mM−1 Fe. The three types of nanoparticles exhibited loading contents of epirubicin of ~3% and drug release percentages of 19% for IO-OAm/mSiO2, 24% for IO-APTES/mSiO2 and 31% for IO/SiO2/mSiO2. The cytotoxicity of drug-loaded and non-loaded most promising nanoparticles was assessed, showing high potential of these platforms for application as anticancer drug carriers.
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•Superparamagnetic iron oxide/mesoporous SiO2 core-shell nanoparticles are prepared.•New ligand exchange and supercritical fluids drying approaches were applied.•Higher % of released epirubicin compared to the literature: up to 30% after 48 h•Potential as T2 contrast agents for MRI, with r2 as high as 63.93 s−1·mM−1 Fe.•Promising biocompatible multifunctional platforms for cancer theranostics
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lithium salts have been in use for the treatment of bipolar disorder for more than 50 years, but their pharmacological mode of action remains a matter of conjecture. Li+ and Mg2+ share many ...physicochemical properties. Not surprisingly, many reported cellular targets for Li+ action involve Mg2+-activated enzymes, which are inhibited by Li+. In this Account, we describe results from our and other laboratories that suggest that a competition mechanism between Li+ and Mg2+ ions for Mg2+-binding sites in cellular components is the underlying theme in putative mechanisms of Li+ action.
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IJS, KILJ, NUK, PNG, UL, UM
The NMR relaxivities of the decatungstolanthanoate core‐shell nanoparticles, prepared by encapsulating Ln(W5O18)29− polyoxometalates (LnPOM) within amorphous silica shells (K9Ln(W5O18)2@SiO2), were ...studied along the Ln series. The relaxivity of GdPOM is slightly higher than for Gd‐DTPA due to second‐sphere relaxation effects, but the values for the other paramagnetic LnPOMs are much smaller due to the short T1e values of their Ln3+‐ions. The NPs have core‐shell spherical structures, with LnPOM‐containing cores with 9.5–28 nm diameters, and 4.0–11.0 nm thick amorphous silica shells. In water suspensions, the NPs have negative zeta potentials (−32.5 to −40.0 mV) and time‐dependent hydrodynamic diameters (31–195 nm) reflecting the formation of aggregates. The relaxivities of GdPOM@SiO2 NPs suspensions (r1=10.97 (mM Gd)−1 s−1, r2=12.02 (mM Gd)−1 s−1, 0.47 T, 25 °C) are considerably larger than for the GdPOM solutions, indicating that their silica shell is significantly porous to water. This increase is limited by the agglomeration of the complexes in the NPs core, limiting their access to water to those at the core surface. Replacing half of the Gd3+ ions by Eu3+ decreases the NPs r1 and r2 relaxivities at 0.47 T to 20 % and 35 % of their initial values, which are still considerable, but does not affect the efficient luminescence properties of the Eu3+ centers. This indicates that the mixed NPs have potential as dual modality MRI/optical imaging contrast agents.
The core‐shell Gd/Eu co‐doped Ln‐polyoxometalates within a silica layer, Gd : Eu(1 : 1)‐POM@SiO2, have suitable water proton relaxivities and photoluminescence properties for use as dual modality MRI and optical imaging contrast agents.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The evaluation of drug's cytotoxicity is a crucial step in the development of new pharmacological compounds. 31P NMR can be a tool for toxicological screening, as it enables the study of drugs' ...cytotoxicity and their effect on cell energy metabolism in a real-time, in a non- invasive and non-destructive way. This paper details a step-by-step protocol to implement a bioreactor system able to maintain cell viability during NMR acquisitions, at high cell densities and for several hours, enabling toxicological evaluation of pharmacological compounds in living cells.
HeLa cells were immobilized in agarose gel threads and continuously perfused with oxygenated medium inside a 5 mm NMR tube. Signals corresponding to intracellular high-energy phosphorous compounds were continuously monitored by 31P NMR to assess cell energy levels, intracellular pH and intracellular free Mg2+ concentrations (Mg2+f) under control and in the presence of two different cytotoxic drugs, calix-NH2 or 5-fluorouracil (5-FU).
The bioreactor system was effective in maintaining cell energy levels as well as intracellular pH and Mg2+f along time, with a good 31P NMR signal to noise ratio. Calix-NH2 and 5-FU decreased cell energy levels by 35% and 39%, respectively, with a negligible increase in intracellular Mg2+f, and without affecting intracellular pH.
The immobilization and perfusion system here detailed, along with 31P NMR, is useful in toxicological evaluation of new pharmacological compounds, enabling the continuous assessment of drugs' effect on energy levels, intracellular pH and Mg2+f in intact cells, for several hours without compromising cell viability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Vanadium compounds have been explored as therapy of diabetes, and most studies have focussed on insulin mimetic effects, i.e. reducing hyperglycemia by improving glucose sensitivity and thus glucose ...uptake in sensitive tissues. We have recently shown that bis(1,2-dimethyl-3-hydroxy-4-pyridinonato)oxidovanadium(IV), VO(dmpp)2, has promising effects when compared to another vanadium compound, bis(maltolato)oxidovanadium(IV), BMOV, and insulin itself, in isolated adipocytes and in vivo in Goto-Kakizaki (GK) rats, an animal model of hereditary type 2 diabetes (T2D). We now have investigated in GK rats whether VO(dmpp)2 also modulates another important defect in T2D, impaired insulin secretion. VO(dmpp)2, but not BMOV, stimulated insulin secretion from isolated GK rat pancreatic islets at high, 16.7mM, but not at low–normal, 3.3mM, glucose concentration. Mechanistic studies demonstrate that the insulin releasing effect of VO(dmpp)2 is due to its interaction with several steps in the stimulus-secretion coupling for glucose, including islet glucose metabolism and K-ATP channels, L-type Ca2+ channels, modulation by protein kinases A and C, as well as the exocytotic machinery. In conclusion, VO(dmpp)2 exhibits properties of interest for treatment of the insulin secretory defect in T2D, in addition to its well-described insulin mimetic activity.
VO(dmpp)2 improves insulin secretion only in hyperglycemic condition, from pancreatic islets of spontaneously diabetic GK rats. As this compound ameliorates the defective glucose-induced insulin secretion in an animal model of type 2 diabetes, it seems to exhibit properties of interest for the treatment of this disease. Display omitted
•Vanadium compounds have been suggested for treatment of type 2 diabetes.•Oxidovanadium(IV) complex of 1,2-dimethyl-3-hydroxy-4-pyridinonato(dmpp) has been studied.•VO(dmpp)2, has shown antidiabetic properties by in vitro and in vivo studies.•Here we show it also improves glucose-induced insulin secretion in GK pancreatic islets.•This promising result corroborates the use of VO(dmpp)2 for treatment of type 2 diabetes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Water soluble phthalocyanines bearing either four PEG500 or four choline substituents in the macrocyclic structure, as well as their Zn(II) and Mn(III) complexes were synthesized. The metal-free and ...Zn(II) complexes present relatively high fluorescence quantum yields (up to 0.30), while the Mn(III) complexes show no fluorescence as a consequence of rapid non-radiative deactivation of the Mn(III) phthalocyanine excited states through low-lying metal based or charge-transfer states.
The effect of DMSO on the aggregation of the phthalocyanines was studied. It was not possible to obtain the Mn(II) complexes by reduction of the corresponding Mn(III) complexes due to the presence of electron donating substituents at the periphery of the phthalocyanines. The 1H NMRD plots of the PEG500 and choline substituted Mn(III)-phthalocyanine complexes are typical of self-aggregated Mn(III) systems with r1 relaxivities of 4.0 and 5.7mM−1s−1 at 20MHz and 25°C. The Mn(III)-phthalocyanine-PEG4 complex shows no significant cytotoxicity to HeLa cell cultures after 2h of incubation up to 2mM concentration. After 24h of cell exposure to the compound, significant toxicity was observed for all the concentrations tested with IC50 of 1.105mM.
Water soluble phthalocyanines bearing either PEG500 or choline substituents were synthesized. Their Zn(II) complexes show quantum yields of 0.13–0.3, while the Mn(III) complexes present r1 relaxivities of 4.0–5.7mM−1s−1, with no significant toxicity to HeLa cell cultures. Display omitted
•Biocompatible metal free, zinc(II) and manganese(III) phthalocyanines were synthesized.•Photophysical and relaxometric studies were done on the Zn(II) and Mn(III) phthalocyanines.•Cytotoxicity studies were performed for one Mn(III) phthalocyanine with HeLa cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
This work reports on highly fluorescent and superparamagnetic bimodal nanoparticles (BNPs) obtained by a simple and efficient method as probes for fluorescence analysis and/or contrast agents for ...MRI. These promising BNPs with small dimensions (ca. 17 nm) consist of superparamagnetic iron oxide nanoparticles (SPIONs) covalently bound with CdTe quantum dots (ca. 3 nm). The chemical structure of the magnetic part of BNPs is predominantly magnetite, with minor goethite and maghemite contributions, as shown by Mössbauer spectroscopy, which is compatible with the x-ray diffraction data. Their size evaluation by different techniques showed that the SPION derivatization process, in order to produce the BNPs, does not lead to a large size increase. The BNPs saturation magnetization, when corrected for the organic content of the sample, is ca. 68 emu g−1, which is only slightly reduced relative to the bare nanoparticles. This indicates that the SPION surface functionalization does not change considerably the magnetic properties. The BNP aqueous suspensions presented stability, high fluorescence, high relaxivity ratio (r2/r1 equal to 25) and labeled efficiently HeLa cells as can be seen by fluorescence analysis. These BNP properties point to their applications as fluorescent probes as well as negative T2-weighted MRI contrast agents. Moreover, their potential magnetic response could also be used for fast bioseparation applications.
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