Rory L. Arrowsmith

Fluorescent copper(II) bis(thiosemicarbazonates): synthesis, structures, electron paramagnetic resonance, radiolabeling, in vitro cytotoxicity and confocal fluorescence microscopy studies.

Copper bis(4-ethyl-3-thiosemicarbazonato) acenaphthenequinone (1) and copper bis(4-methyl-3-thiosemicarbazonato) acenaphthenequinone (2) are synthesized and characterized in solution, in the solid state, and radiolabeled. Serum-protein binding radioassays show good stability in solution and about 25 % binding to protein over 1 h, which is comparable with the hypoxia selective tracer [(64)Cu(ATSM)]. Cyclic voltammetry shows fast and reversible reduction at redox potentials similar to the values known for hypoxia-selective copper compounds. However, despite this, complex 1 does not show any hypoxic-selective uptake in HeLa cells over 1-h standard assays. Possible reasons for this are studied by using the intrinsic fluorescence of the Cu(II) complexes to determine the cellular distributions and uptake mechanism by confocal microscopy. The complexes are found to bind to the external cell membrane and disperse evenly in the cytoplasm only after a very slow cell internalization (>1 h). No significant changes in distribution are observed by fluorescence imaging under hypoxic conditions. The rate of localization in the cytoplasm contrasts with their Zn(II) analogues, which are known to have fast cell uptake (up to 20 min) and a clear localization in lysosomes and mitochondria. The cytotoxicity mechanism of 1 over 24 h against a number of adherent cell lines is seen to be by membrane disruption and is of a comparable magnitude to that of [Cu(ATSM)], as demonstrated by methyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays.

Synthesis and evaluation of a boronate-tagged 1,8-naphthalimide probe for fluoride recognition

A biocompatible fluoride receptor has been developed where the interaction between the boronic acid ester and amine (NH) results in fluoride ion selectivity and enhanced fluorescence quenching.

Fluorescent gallium and indium bis(thiosemicarbazonates) and their radiolabelled analogues: Synthesis, structures and cellular confocal fluorescence imaging investigations

New fluorescent and biocompatible aromatic Ga(III)- and In(III)-bis(thiosemicarbazonato) complexes for dual mode optical and PET or SPECT molecular imaging have been synthesised via a synthetic method based on transmetallation reactions from Zn(II) precursors. Complexes have been fully characterised in the solid state by single crystal X-ray diffraction and in solution by spectroscopic methods (UV/Vis, fluorescence, (1)H and (13)C{(1)H} NMR). The bis(thiosemicarbazones) radiolabelled rapidly in high yields under mild conditions with (111)In (a gamma and Auger emitter for SPECT imaging and radiotherapy with t(1/2) = 2.8 d) and (68)Ga (a generator-available positron emitter for PET imaging with t(1/2) = 68 min). Cytotoxicity and biolocalisation studies using confocal fluorescence imaging and fluorescence lifetime imaging (FLIM) techniques have been used to study their in vitro activities and stabilities in HeLa and PC-3 cells to ascertain their suitability as synthetic scaffolds for future multimodality molecular imaging in cancer diagnosis and therapy. The observation that the indium complexes show certain nuclear uptake could be of relevance towards developing (111)In therapeutic agents based on Auger electron emission to induce DNA damage.

Towards nanomedicines: design protocols to assemble, visualize and test carbon nanotube probes for multi-modality biomedical imaging

Nanomedicine is an interdisciplinary field, still in its infancy, where an accurate scientific assessment of potential risks and benefits is urgently needed, as is the engagement of end users and the public in this facet of the nanotechnology debate. There is increasing interest in improving our understanding of the interactions between nanomaterials and living systems, with regard to both the underlying chemistry and the physics of effects on the nanoscale. Ultimately, such knowledge promises new vistas for designing the ‘smart’ medicines of the future, of which targeted personalized drugs are the holy grail. Imaging and therapeutic components, including metallic radioisotopes, semiconductor quantum dots and magnetic materials, may be used to construct ‘nanocarriers’ (by encapsulation or conjugation) by rapid and simple (covalent and supramolecular) chemistry. The biomedical functions of the resulting materials are as yet largely unexplored. Encapsulation in nanocarriers could achieve delivery of the reagents (imaging and therapeutic drugs) to the sites of action in the body, while minimizing systemic toxicity and enzymatic degradation. These functional systems have the potential to become a general solution in drug delivery. Here we review recent developments concerning the applications of nanoparticles, including carbon nanotubes, as synthetic scaffolds for designing nanomedicines. This article will also focus on how understanding and design at the molecular level could help interdisciplinary teams develop research towards new diagnostics and therapeutics both in the short and the long term.

Hydrothermal conversion of one-photon-fluorescent poly-(4-vinylpyridine) into two-photon-fluorescent carbon nanodots

A novel two-photon-fluorescent N,O-heteroatom-rich carbon nanomaterial has been synthesized and characterized. The new carbon nanoparticles were produced by hydrothermal conversion from a one-photon-fluorescent poly(4-vinylpyridine) precursor (P4VP). The carbonized particles (cP4VP dots) with nonuniform particle diameter (ranging from sub-6 to 20 nm with some aggregates up to 200 nm) exhibit strong fluorescence properties in different solvents and have also been investigated for applications in cell culture media. The cP4VP dots retain their intrinsic fluorescence in a cellular environment and exhibit an average excited-state lifetime of 2.0 ± 0.9 ns in the cell. The cP4VP dots enter HeLa cells and do not cause significant damage to outer cell membranes. They provide one-photon or two-photon fluorescent synthetic scaffolds for imaging applications and/or drug delivery.

New developments in the biomedical chemistry of metal complexes: from small molecules to nanotheranostic design

Recent advancements in bioimaging involving metal complexes with a focus on organometallic and coordination complexes are discussed with the aim to highlight their applications towards a new era in diagnostics: personalised medicine. The use of small molecules encapsulated within or attached to nanostructures for multimodal imaging and/or theranostic applications will be also discussed. Probes for imaging methods such as luminescence, PET, SPECT and MRI will be included as each modality possessing its own advantages and limitations. The current drive towards combination of techniques which will lead to complementary information on processes in cells and tissues and a more accurate, earlier diagnosis of tumours will also be discussed. The possibility of simultaneous diagnosis and therapy draws closer the advancement of probes from ‘bench to bedside’ and will be underlined in this review.

Re and 99m Tc complexes of BodP3 - multi-modality imaging probes†

A fluorescent tridentate phosphine, BodP3 (2), forms rhenium complexes which effectively image cancer cells. Related technetium analogues are also readily prepared and have potential as dual SPECT/fluorescent biological probes.

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 ‘cold’ and ‘hot’ biological assays and were investigated using laser scanning confocal microscopy, flow cytometry and radioactive cell retention studies under normoxia and hypoxia. 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.

Intrinsically fluorescent bis(thiosemicarbazonates) with high kinetic stability in biological environments: synthetic scaffolds for optical/PET or SPECT dual-modality imaging agent

On 4 December 1913, the journal Nature published a letter by Frederick Soddy, of the University of Glasgow, in which the term isotope was publicly used for the first time. Soddy had been at Glasgow since 1904 and realized the chemical identity of ‘mesothorium’ (228Ra—which Soddy separated from thorium minerals) and Marie Curie’s radium (226Ra—from uranium minerals). Soddy was awarded the Nobel Prize for Chemistry in 1921, largely for this work. A number of historical radioactive samples (including Soddy samples) survive at Glasgow, as well as some of his equipment, and these provide a rare glimpse into the birth of radiochemistry. High precision gamma-ray spectrometry has been carried out on them, and together with archival research, this provides new insights into their preparation and history. Since Soddy’s breakthrough, the ratio of known isotopes to elements has grown from 1 to nearly 27!Isotopic labelling with heavy hydrogen isotopes (D2 and T2) is widely used as a means to monitor the biological fate of a potential drug molecule and represents a particularly industry-facing example of chemoselective organometallic catalysis. Consequently, preliminary studies from our laboratory have allowed expedient access to a series of novel iridium complexes, such as 2, that are able to catalyse the ortho-deuteration of various coordinating functionalities and pharmacophores, such as ketones, amides and nitro compounds 2 (Scheme 1). As part of our latest studies, we recently reported an efficient protocol for ortho-deuteration using more readily accessible Ir(I)chloro-carbene complexes. Turning to more challenging substrate classes, the utility of bench-stable catalysts such as 5 has now evolved to deliver the first highly effective strategy for the ortho-deuteration of primary sulfonamides at room temperature (Scheme 2). Additionally, we have used experimental and computational methods in parallel to explain the origins of observed chemoselectivity in labelling multi-functional drug molecules like 7, highlighting the importance of substrate–complex interactions during complexation. The details of all such studies will be delineated in this lecture.