Results
- Showing results for:
- Reset all filters
Search results
-
Journal articleBoltersdorf T, Ansari J, Senchenkova EY, et al., 2020,
Targeting of formyl peptide receptor 2 for in vivo imaging of acute vascular inflammation
, Theranostics, Vol: 10, Pages: 6599-6614, ISSN: 1838-7640Inflammatory conditions are associated with a variety of diseases and can significantly contribute to their pathophysiology. Neutrophils are recognised as key players in driving vascular inflammation and promoting inflammation resolution. As a result, neutrophils, and specifically their surface formyl peptide receptors (FPRs), are attractive targets for non-invasive visualization of inflammatory disease states and studying mechanistic details of the process.Methods: A small-molecule Formyl Peptide Receptor 2 (FPR2/ALX)-targeted compound was combined with two rhodamine-derived fluorescent tags to form firstly, a targeted probe (Rho-pip-C1) and secondly a targeted, pH-responsive probe (Rho-NH-C1) for in vivo applications. We tested internalization, toxicity and functional interactions with neutrophils in vitro for both compounds, as well as the fluorescence switching response of Rho-NH-C1 to neutrophil activation. Finally, in vivo imaging (fluorescent intravital microscopy [IVM]) and therapeutic efficacy studies were performed in an inflammatory mouse model.Results: In vitro studies showed that the compounds bound to human neutrophils via FPR2/ALX without causing internalization at relevant concentrations. Additionally, the compounds did not cause toxicity or affect neutrophil functional responses (e.g. chemotaxis or transmigration). In vivo studies using IVM showed Rho-pip-C1 bound to activated neutrophils in a model of vascular inflammation. The pH-sensitive (“switchable”) version termed Rho-NH-C1 validated these findings, showing fluorescent activity only in inflammatory conditions.Conclusions: These results indicate a viable design of fluorescent probes that have the ability to detect inflammatory events by targeting activated neutrophils.
-
Journal articleWang X, Bennett TLR, Ismael A, et al., 2020,
Scale-up of room-temperature constructive quantum interference from single molecules to self-assembled molecular-electronic films
, Journal of the American Chemical Society, Vol: 142, Pages: 8555-8560, ISSN: 0002-7863The realization of self-assembled molecular-electronic films, whose room-temperature transport properties are controlled by quantum interference (QI), is an essential step in the scale-up of QI effects from single molecules to parallel arrays of molecules. Recently, the effect of destructive QI (DQI) on the electrical conductance of self-assembled monolayers (SAMs) has been investigated. Here, through a combined experimental and theoretical investigation, we demonstrate chemical control of different forms of constructive QI (CQI) in cross-plane transport through SAMs and assess its influence on cross-plane thermoelectricity in SAMs. It is known that the electrical conductance of single molecules can be controlled in a deterministic manner, by chemically varying their connectivity to external electrodes. Here, by employing synthetic methodologies to vary the connectivity of terminal anchor groups around aromatic anthracene cores, and by forming SAMs of the resulting molecules, we clearly demonstrate that this signature of CQI can be translated into SAM-on-gold molecular films. We show that the conductance of vertical molecular junctions formed from anthracene-based molecules with two different connectivities differ by a factor of approximately 16, in agreement with theoretical predictions for their conductance ratio based on CQI effects within the core. We also demonstrate that for molecules with thioether anchor groups, the Seebeck coefficient of such films is connectivity dependent and with an appropriate choice of connectivity can be boosted by ∼50%. This demonstration of QI and its influence on thermoelectricity in SAMs represents a critical step toward functional ultra-thin-film devices for future thermoelectric and molecular-scale electronics applications.
-
Journal articleClough TJ, Baxan N, Coakley EJ, et al., 2020,
Synthesis and in vivo behaviour of an exendin-4-based MRI probe capable of beta-cell-dependent contrast enhancement in the pancreas
, Dalton Transactions: an international journal of inorganic chemistry, Vol: 49, Pages: 4732-4740, ISSN: 1477-9226Global rates of diabetes mellitus are increasing, and treatment of the disease consumes a growing proportion of healthcare spending across the world. Pancreatic β-cells, responsible for insulin production, decline in mass in type 1 and, to a more limited degree, in type 2 diabetes. However, the extent and rate of loss in both diseases differs between patients resulting in the need for the development of novel diagnostic tools, which could quantitatively assess changes in mass of β-cells over time and potentially lead to earlier diagnosis and improved treatments. Exendin-4, a potent analogue of glucagon-like-peptide 1 (GLP-1), binds to the receptor GLP-1R, whose expression is enriched in β-cells. GLP-1R has thus been used in the past as a means of targeting probes for a wide variety of imaging modalities to the endocrine pancreas. However, exendin-4 conjugates designed specifically for MRI contrast agents are an under-explored area. In the present work, the synthesis and characterization of an exendin-4-dota(ga)-Gd(III) complex, GdEx, is reported, along with its in vivo behaviour in healthy and in β-cell-depleted C57BL/6J mice. Compared to the ubiquitous probe, [Gd(dota)]−, GdEx shows selective uptake by the pancreas with a marked decrease in accumulation observed after the loss of β-cells elicited by deleting the microRNA processing enzyme, DICER. These results open up pathways towards the development of other targeted MRI contrast agents based on similar chemistry methodology.
-
Journal articleJiang L, Lung HL, Huang T, et al., 2020,
Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn<SUP>2+</SUP>-chelating function (vol 116, pg 26614, 2019)
, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 5542-5542, ISSN: 0027-8424- Author Web Link
- Cite
- Citations: 2
-
Journal articleGawne PJ, Clarke F, Turjeman K, et al., 2020,
PET imaging of liposomal glucocorticoids using Zr-89-oxine: theranostic applications in inflammatory arthritis
, Theranostics, Vol: 10, Pages: 3867-3879, ISSN: 1838-7640The encapsulation of Glucocorticoids (GCs) into long-circulating liposomes (LCLs) is a proven strategy to reduce the side effects of glucocorticoids and improve the treatment of inflammatory diseases, such as rheumatoid arthritis (RA). With the aim of supporting the development of GC-loaded LCLs, and potentially predict patient response to therapy clinically, we evaluated a direct PET imaging radiolabelling approach for preformed GC-LCLs in an animal model of human inflammatory arthritis.Methods: A preformed PEGylated liposomal methylprednisolone hemisuccinate (NSSL-MPS) nanomedicine was radiolabelled using [89Zr]Zr(oxinate)4 (89Zr-oxine), characterised and tracked in vivo using PET imaging in a K/BxN serum-transfer arthritis (STA) mouse model of inflammatory arthritis and non-inflamed controls. Histology and joint size measurements were used to confirm inflammation. The biodistribution of 89Zr-NSSL-MPS was compared to that of free 89Zr in the same model. A therapeutic study using NSSL-MPS using the same time points as the PET/CT imaging was carried out.Results: The radiolabelling efficiency of NSSL-MPS with [89Zr]Zr(oxinate)4 was 69 ± 8 %. PET/CT imaging of 89Zr-NSSL-MPS showed high uptake (3.6 ± 1.5 % ID; 17.4 ± 9.3 % ID/mL) at inflamed joints, with low activity present in non-inflamed joints (0.5 ± 0.1 % ID; 2.7 ± 1.1 % ID/mL). Importantly, a clear correlation between joint swelling and high 89Zr-NSSL-MPS uptake was observed, which was not observed with free 89Zr. STA mice receiving a therapeutic dose of NSSL-MPS showed a reduction in inflammation at the time points used for the PET/CT imaging compared with the control group.Conclusions: PET imaging was used for the first time to track a liposomal glucocorticoid, showing high uptake at visible and occult inflamed sites and a good correlation with the degree of inflammation. A subsequent therapeutic response matching imaging time points in the same model demonstrated the potentia
-
Journal articleMorse SV, Boltersdorf T, Harriss BI, et al., 2020,
Neuron labeling with rhodamine-conjugated Gd-based MRI contrast agents delivered to the brain via focused ultrasound
, Theranostics, Vol: 10, Pages: 2659-2674, ISSN: 1838-7640Gadolinium-based magnetic resonance imaging contrast agents can provide information regarding neuronal function, provided that these agents can cross the neuronal cell membrane. Such contrast agents are normally restricted to extracellular domains, however, by attaching cationic fluorescent dyes, they can be made cell-permeable and allow for both optical and magnetic resonance detection. To reach neurons, these agents also need to cross the blood-brain barrier. Focused ultrasound combined with microbubbles has been shown to enhance the permeability of this barrier, allowing molecules into the brain non-invasively, locally and transiently. The goal of this study was to investigate whether combining fluorescent rhodamine with a gadolinium complex would form a dual-modal contrast agent that could label neurons in vivo when delivered to the mouse brain with focused ultrasound and microbubbles.Methods: Gadolinium complexes were combined with a fluorescent, cationic rhodamine unit to form probes with fluorescence and relaxivity properties suitable for in vivo applications. The left hemisphere of female C57bl/6 mice (8-10 weeks old; 19.07 ± 1.56 g; n = 16) was treated with ultrasound (centre frequency: 1 MHz, peak-negative pressure: 0.35 MPa, pulse length: 10 ms, repetition frequency: 0.5 Hz) while intravenously injecting SonoVue microbubbles and either the 1 kDa Gd(rhodamine-pip-DO3A) complex or a conventionally-used lysine-fixable Texas Red® 3 kDa dextran. The opposite right hemisphere was used as a non-treated control region. Brains were then extracted and either sectioned and imaged via fluorescence or confocal microscopy or imaged using a 9.4 T magnetic resonance imaging scanner. Brain slices were stained for neurons (NeuN), microglia (Iba1) and astrocytes (GFAP) to investigate the cellular localization of the probes.Results: Rhodamine fluorescence was detected in the left hemisphere of all ultrasound treated mice, while none was detected in the right contr
-
Journal articleSmith AJ, Osborne BE, Keeling GP, et al., 2020,
DO2A-based ligands for gallium-68 chelation: synthesis, radiochemistry and <i>ex vivo</i> cardiac uptake
, DALTON TRANSACTIONS, Vol: 49, Pages: 1097-1106, ISSN: 1477-9226- Author Web Link
- Cite
- Citations: 9
-
Journal articleJiang L, Lung HL, Huang T, et al., 2019,
Reactivation of Epstein Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function.
, Proceedings of the National Academy of Sciences of USA, Vol: 116, Pages: 26614-26624, ISSN: 0027-8424Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome, and is the only viral protein expressed in nearly all forms of EBV latency and EBV-associated diseases including numerous cancer types. To our knowledge, no specific agent against Epstein Barr virus (EBV) genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+- responsive probe (ZRL5P4), which alone could reactivate EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The new bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that the treatment with ZRL5P4-alone could reactivate the EBV lytic induction by expressing the early and late EBV lytic genes/proteins. The lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our new probe ZRL5P4 represents the first EBV protein-specific agent to potently reactivate EBV from latency, leading to the shrinkage of EBV-positive tumours, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.
-
Journal articleMcCluskey S, Haslop A, Coello C, et al., 2019,
Imaging chemotherapy induced acute cardiotoxicity with 18F-labelled lipophilic cations
, Journal of Nuclear Medicine, Vol: 60, Pages: 1750-1756, ISSN: 1535-5667Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation positron emission tomography (PET) tracers may be suitable for early detection of cardiotoxicity. This study aims to evaluate an 18F-labelled lipophilic phosphonium cation e.g. 18F-Mitophos, as a cardiac imaging agent, comparing it to leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin (DOX) model.
-
Journal articleBoltersdorf T, Ansari J, Senchenkova EY, et al., 2019,
Development, characterisation and in vitro evaluation of lanthanide-based FPR2/ALX-targeted imaging probes.
, Dalton Trans, Vol: 48, Pages: 16764-16775We report the design, preparation and characterisation of three small-molecule, Formyl Peptide Receptor (FPR)-targeted lanthanide complexes (Tb·14, Eu·14 and Gd·14). Long-lived, metal-based emission was observed from the terbium complex (τH2O = 1.9 ms), whereas only negligible lanthanide signals were detected in the europium analogue. Ligand-centred emission was investigated using Gd·14 at room temperature and 77 K, leading to the postulation that metal emission may be sensitised via a ligand-based charge transfer state of the targeting Quin C1 unit. Comparatively high longitudinal relaxivity values (r1) for octadentate metal complexes of Gd·14 were determined (6.9 mM-1 s-1 at 400 MHz and 294 K), which could be a result of a relative increase in twisted square antiprism (TSAP) isomer prevalence compared to typical DOTA constructs (as evidenced by NMR spectroscopy). In vitro validation of concentration responses of Tb·14via three key neutrophil functional assays demonstrated that the inflammatory responses of neutrophils (i.e. chemotaxis, transmigration and granular release) remained unchanged in the presence of specific concentrations of the compound. Using a time-resolved microscopy set-up we were able to observe binding of the Tb·14 probe to stimulated human neutrophils around the cell periphery, while in the same experiment with un-activated neutrophils, no metal-based signals were detected. Our results demonstrate the utility of Tb·14 for time-resolved microscopy with lifetimes several orders of magnitude longer than autofluorescent signals and a preferential uptake in stimulated neutrophils.
-
Journal articleXie C, Chau H-F, Zhang J-X, et al., 2019,
Bladder Cancer Photodynamic Therapeutic Agent with Off-On Magnetic Resonance Imaging Enhancement
, ADVANCED THERAPEUTICS, Vol: 2- Author Web Link
- Cite
- Citations: 18
-
Journal articleMundil R, Wilson LE, Schaarschmidt D, et al., 2019,
Redox-switchable α-diimine palladium catalysts for control of polyethylene topology
, Polymer, Vol: 179, ISSN: 0032-3861A series of palladium complexes bearing ferrocene substituted α-diimine ligands was synthesized and investigated for ethene polymerization at different conditions to modulate the extent of “chain-walking” mechanism and regulate branching and topology of resulting polyethylenes. All ferrocene substituted complexes catalyzed living/controlled ethene polymerization. The ability of ferrocene substituted palladium complexes to provide polyethylenes with dendritic topology was proved by measuring their Mark-Houwink plots. In-situ chemical oxidation of ferrocene moieties via silver triflate was used to affect the catalyst electronic structure and support the “chain-walking” mechanism. Oxidation of palladium catalyst led to its destabilization while the catalytic activity of newly formed sites was substantially increased. It was demonstrated that catalyst oxidation is a powerful tool to regulate the topology of resulting polyethylenes.
-
Conference paperBoyle J, Seneviratne A, Han Y, et al., 2019,
VERTEBRATE HEMATOMA RESOLUTION IS DIRECTED BY ACTIVATING TRANSCRIPTION FACTOR 1 (ATF1) AND ADENOSINE-MONOPHOSPHATE-ACTIVATED-PROTEIN-KINASE (AMPK)
, 87th Congress of the European-Atherosclerosis-Society (EAS), Publisher: ELSEVIER IRELAND LTD, Pages: E246-E246, ISSN: 0021-9150 -
Journal articleWang L, Long NJ, Li L, et al., 2019,
Multi-functional bismuth-doped bioglasses: combining bioactivity and photothermal response for bone tumor treatment and tissue repair (vol 7, 1, 2018)
, LIGHT-SCIENCE & APPLICATIONS, Vol: 8, ISSN: 2047-7538 -
Journal articleMiller P, Apps S, Long N, 2019,
Cobalt(-I) triphos dinitrogen complexes: activation and silyl-functionalisation of N2
, Chemical Communications, Vol: 55, Pages: 6579-6582, ISSN: 1359-7345The cobalt dinitrogen complexes [{(EP3Ph)Co(μ-N2)}2Mg(THF)4], with triphos ligand scaffolds (EP3Ph, E = N or CMe), were prepared via two electron reductions of the Co(I) precursors [CoCl(EP3Ph)]. Both complexes showed high degrees of N2 activation owing to the formation of a rare M–NN–Mg–NN–M bridging-magnesium core. These systems showed further N2 functionalisation reactivity by silylation, forming silyldiazenido complexes [(EP3Ph)Co(NNSiMe3)].
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.
Contact
Professor Nick Long
Email: n.long@imperial.ac.uk
Telephone: +44 (0)20 7594 5781
Location
501J
Molecular Sciences Research Hub
White City Campus
