12 research outputs found
Investigations into New Functionalised Thiosemicarbazones and Related Carbon Nanohybrids for the Imaging of Prostate Cancer
Applications of âHotâ and âColdâ Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging
Novel rhenium(V) nitride complexes with dithiocarbimate ligands: A synchrotron X-ray and DFT structural investigation
Correction:Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: Structural investigations and cellular uptake under hypoxia (Dalton Transactions (2016) 45 (144-155))
We report the microwave synthesis of several bis(thiosemicarbazones) and the rapid gallium-68 incorporation to give the corresponding metal complexes. These proved kinetically stable under âcoldâ and âhotâ biological assays and were investigated using laser scanning confocal microscopy, flow cytometry and radioactive cell retention studies under normoxia and hypoxia. (68)Ga complex retention was found to be 34% higher in hypoxic cells than in normoxic cells over 30 min, further increasing to 53% at 120 min. Our data suggests that this class of gallium complexes show hypoxia selectivity suitable for imaging in living cells and in vivo tests by microPET in nude athymic mice showed that they are excreted within 1 h of their administration
Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases
Hypoxia has been identified as one of the hallmarks of tumor environments and a prognosis factor in many cancers. The development of ideal chemical probes for imaging and sensing of hypoxia remains elusive. Crucial characteristics would include a measurable response to subtle variations of pO2 in living systems and an ability to accumulate only in the areas of interest (e.g., targeting hypoxia tissues) whilst exhibiting kinetic stabilities in vitro and in vivo. A sensitive probe would comprise platforms for applications in imaging and therapy for non-communicable diseases (NCDs) relying on sensitive detection of pO2. Just a handful of probes for the in vivo imaging of hypoxia [mainly using positron emission tomography (PET)] have reached the clinical research stage. Many chemical compounds, whilst presenting promising in vitro results as oxygen-sensing probes, are facing considerable disadvantages regarding their general application in vivo. The mechanisms of action of many hypoxia tracers have not been entirely rationalized, especially in the case of metallo-probes. An insight into the hypoxia selectivity mechanisms can allow an optimization of current imaging probes candidates and this will be explored hereby. The mechanistic understanding of the modes of action of coordination compounds under oxygen concentration gradients in living cells allows an expansion of the scope of compounds toward in vivo applications which, in turn, would help translate these into clinical applications. We summarize hereby some of the recent research efforts made toward the discovery of new oxygen sensing molecules having a metal-ligand core. We discuss their applications in vitro and/or in vivo, with an appreciation of a plethora of molecular imaging techniques (mainly reliant on nuclear medicine techniques) currently applied in the detection and tracing of hypoxia in the preclinical and clinical setups. The design of imaging/sensing probe for early-stage diagnosis would longer term avoid invasive procedures providing platforms for therapy monitoring in a variety of NCDs and, particularly, in cancers
Corrigendum: Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases
Applications of âHotâ and âColdâ Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging
The applications of coordination chemistry to molecular imaging has become a matter of intense research over the past 10 years. In particular, the applications of bis(thiosemicarbazonato) metal complexes in molecular imaging have mainly been focused on compounds with aliphatic backbones due to the in vivo imaging success of hypoxic tumors with PET (positron emission tomography) using 64CuATSM [copper (diacetyl-bis(N4-methylthiosemicarbazone))]. This compound entered clinical trials in the US and the UK during the first decade of the 21st century for imaging hypoxia in head and neck tumors. The replacement of the ligand backbone to aromatic groups, coupled with the exocyclic N's functionalization during the synthesis of bis(thiosemicarbazones) opens the possibility to use the corresponding metal complexes as multimodal imaging agents of use, both in vitro for optical detection, and in vivo when radiolabeled with several different metallic species. The greater kinetic stability of acenaphthenequinone bis(thiosemicarbazonato) metal complexes, with respect to that of the corresponding aliphatic ATSM complexes, allows the stabilization of a number of imaging probes, with special interest in âcoldâ and âhotâ Cu(II) and Ga(III) derivatives for PET applications and 111In(III) derivatives for SPECT (single-photon emission computed tomography) applications, whilst Zn(II) derivatives display optical imaging properties in cells, with enhanced fluorescence emission and lifetime with respect to the free ligands. Preliminary studies have shown that gallium-based acenaphthenequinone bis(thiosemicarbazonato) complexes are also hypoxia selective in vitro, thus increasing the interest in them as new generation imaging agents for in vitro and in vivo applications.</p
Correction:Microwave gallium-68 radiochemistry for kinetically stable bis(thiosemicarbazone) complexes: Structural investigations and cellular uptake under hypoxia (Dalton Transactions (2016) 45 (144-155))
Shedding Light Onto the Nature of Iron DecoratedGraphene and Graphite Oxide Nanohybrids for CO2Conversion at Atmospheric Pressure
[EN] We report on the design and testing of new graphite and graphene oxideâbased extended Ïâconjugated synthetic scaffolds for applications in sustainable chemistry transformations. Nanoparticleâfunctionalised carbonaceous catalysts for new Fischer Tropsch and Reverse GasWater Shift (RGWS) transformations were prepared: functional graphene oxides emerged from graphite powders via an adapted Hummer's method and subsequently impregnated with uniformâsized nanoparticles. Then the resulting nanomaterials were imaged by TEM, SEM, EDX, AFM and characterised by IR, XPS and Raman spectroscopies prior to incorporation of Pd(II) promoters and further microscopic and spectroscopic analysis. Newly synthesised 2D and 3D layered nanostructures incorporating carbonâsupported iron oxide nanoparticulate preâcatalysts were tested, upon hydrogen reduction inâ
situ, for the conversion of CO2 to CO as well as for the selective formation of CH4 and longer chain hydrocarbons. The reduction reaction was also carried out and the catalytic species isolated and fully characterised. The catalytic activity of a graphene oxideâsupported iron oxide preâcatalyst converted CO2 into hydrocarbons at different temperatures (305, 335, 370 and 405â°C), and its activity compared well with that of the analogues supported on graphite oxide, the 3âdimensional material precursor to the graphene oxide. Investigation into the use of graphene oxide as a framework for catalysis showed that it has promising activity with respect to reverse gas water shift (RWGS) reaction of CO2 to CO, even at the low levels of catalyst used and under the rather mild conditions employed at atmospheric pressure. Whilst the ÎłâFe2O3 decorated graphene oxideâbased preâcatalyst displays fairly constant activity up to 405â°C, it was found by GCâMS analysis to be unstable with respect to decomposition at higher temperatures. The addition of palladium as a promoter increased the activity of the iron functionalised graphite oxide in the RWGS. The activity of graphene oxide supported catalysts was found to be enhanced with respect to that of ironâfunctionalised graphite oxide with, or without palladium as a promoter, and comparable to that of Fe@carbon nanotubeâbased systems tested under analogous conditions. These results display a significant step forward for the catalytic activity estimations for the iron functionalised and rapidly processable and scalable graphene oxide. The hereby investigated phenomena are of particular relevance for the understanding of the intimate surface morphologies and the potential role of nonâcovalent interactions in the iron oxideâgraphene oxide networks, which could inform the design of nanoâmaterials with performance in future sustainable catalysis applications.This work was financially supported by Science & Technologies Facilities Council, EPSRC (EP/K017160/1, EPGO3768X/1, EP/L016354/1, EP/H04630511) and the ERC Consolidator grant scheme (617107 O2SENSE to Sofia Pascu) and University of Bath. Dr David G. Calatayud thanks the FundaciĂłn General CSIC for funding (ComFuturo Program). We thank Drs James Tyson, Vincenzo Mirabello and Justin O'Byrne (Bath University) for their collaborative support, helpful discussions and particularly for the assistance with initial batches of GO and thermally reduced GO synthesis, PXRD and Raman spectroscopy.Peer reviewe
Structural and Functional Diversity in Rigid Thiosemicarbazones with Extended Aromatic Frameworks: Microwave-Assisted Synthesis and Structural Investigations
The long-standing interest in thiosemicarbazones (TSCs)
has been
largely driven by their potential toward theranostic applications
including cellular imaging assays and multimodality imaging. We focus
herein on the results of our new investigations into: (a) the structural
chemistry of a family of rigid mono(thiosemicarbazone) ligands characterized
by extended and aromatic backbones and (b) the formation of their
corresponding thiosemicarbazonato Zn(II) and Cu(II) metal complexes.
The synthesis of new ligands and their Zn(II) complexes was performed
using a rapid, efficient and straightforward microwave-assisted method
which superseded their preparation by conventional heating. We describe
hereby new microwave irradiation protocols that are suitable for both
imine bond formation reactions in the thiosemicabazone ligand synthesis
and for Zn(II) metalation reactions. The new thiosemicarbazone ligands,
denoted HL, mono(4-R-3-thiosemicarbazone)quinone,
and their corresponding Zn(II) complexes, denoted ZnL2,
mono(4-R-3-thiosemicarbazone)quinone, where R = H,
Me, Ethyl, Allyl,
and Phenyl, quinone = acenapthnenequinone (AN), aceanthrenequinone
(AA), phenanthrenequinone (PH), and pyrene-4,5-dione (PY) were isolated
and fully characterized spectroscopically and by mass spectrometry.
A plethora of single crystal X-ray diffraction structures were obtained
and analyzed and the geometries were also validated by DFT calculations.
The Zn(II) complexes presented either distorted octahedral geometry
or tetrahedral arrangements of the O/N/S donors around the metal center.
The modification of the thiosemicarbazide moiety at the exocyclic
N atoms with a range of organic linkers was also explored, opening
the way to bioconjugation protocols for these compounds. The radiolabeling
of these thiosemicarbazones with 64Cu was achieved under
mild conditions for the first time: this cyclotron-available radioisotope
of copper (t1/2 = 12.7 h; ÎČ+ 17.8%;
ÎČâ 38.4%) is well-known for its proficiency in positron
emission tomography (PET) imaging and for its theranostic potential,
on the basis of the preclinical and clinical cancer research of established
bis(thiosemicarbazones), such as the hypoxia tracer 64Cu-labeled
copper(diacetyl-bis(N4-methylthiosemicarbazone)],
[64Cu]Cu(ATSM). Our labeling reactions proceeded in high
radiochemical incorporation (>80% for the most sterically unencumbered
ligands) showing promise of these species as building blocks for theranostics
and synthetic scaffolds for multimodality imaging probes. The corresponding
âcoldâ Cu(II) metalations were also performed under
the mild conditions mimicking the radiolabeling protocols. Interestingly,
room temperature or mild heating led to Cu(II) incorporation in the
1:1, as well as 1:2 metal: ligand ratios in the new complexes, as
evident from extensive mass spectrometry investigations backed by
EPR measurements, and the formation of Cu(L)2-type species
prevails, especially for the AN-Ph thiosemicarbazone
ligand (Lâ). The cytotoxicity levels of a selection
of ligands and Zn(II) complexes in this class were further tested
in commonly used human cancer cell lines (HeLa, human cervical cancer
cells, and PC-3, human prostate cancer cells). Tests showed that their
IC50 levels are comparable to that of the clinical drug
cis-platin, evaluated under similar conditions. The cellular internalizations
of the selected ZnL2-type compounds Zn(AN-Allyl)2, Zn(AA-Allyl)2, Zn(PH-Allyl)2, and Zn(PY-Allyl)2 were evaluated
in living PC-3 cells using laser confocal fluorescent spectroscopy
and these experiments showed exclusively cytoplasmic distributions