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  • Journal article
    Gawne PJ, Clarke F, Turjeman K, Cope AP, Long NJ, Barenholz Y, Terry SYA, de Rosales RTMet al., 2020,

    PET imaging of liposomal glucocorticoids using Zr-89-oxine: theranostic applications in inflammatory arthritis

    , Theranostics, Vol: 10, Pages: 3867-3879, ISSN: 1838-7640

    The 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 article
    Morse SV, Boltersdorf T, Harriss BI, Chan TG, Baxan N, Hee Seok J, Pouliopoulos AN, Choi J, Long NJet 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: 1838-7640

    Gadolinium-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 article
    Smith AJ, Osborne BE, Keeling GP, Blower PJ, Southworth R, Long NJet 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
  • Journal article
    Jiang L, Lung HL, Huang T, Lan R, Zha S, Chan LS, Thor W, Tsoi T, Chau H, Boreström C, Cobb S, Tsao SW, Bian Z, Law G, Wong W, Tai WC, Chau YW, Du Y, Tang LHX, Chiang AKS, Middeldorp JM, Lo K, Mak N, Long N, Wong Ket 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: 0027-8424

    Epstein-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 article
    McCluskey S, Haslop A, Coello C, Gunn R, Tate E, Southworth R, Plisson C, Long NJ, Wells Let al., 2019,

    Imaging chemotherapy induced acute cardiotoxicity with 18F-labelled lipophilic cations

    , Journal of Nuclear Medicine, Vol: 60, Pages: 1750-1756, ISSN: 1535-5667

    Many 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 article
    Boltersdorf T, Ansari J, Senchenkova EY, Jiang L, White AJP, Coogan M, Gavins FNE, Long NJet al., 2019,

    Development, characterisation and in vitro evaluation of lanthanide-based FPR2/ALX-targeted imaging probes.

    , Dalton Trans, Vol: 48, Pages: 16764-16775

    We 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 article
    Xie C, Chau H-F, Zhang J-X, Tong S, Jiang L, Fok W-Y, Lung H-L, Zha S, Zou R, Jiao J, Ng C-F, Ma P, Zhang J, Lin J, Shiu KK, Bunzli J-CG, Wong W-K, Long NJ, Law G-L, Wong K-Let al., 2019,

    Bladder Cancer Photodynamic Therapeutic Agent with Off-On Magnetic Resonance Imaging Enhancement

    , ADVANCED THERAPEUTICS, Vol: 2
  • Journal article
    Mundil R, Wilson LE, Schaarschmidt D, Císařová I, Merna J, Long NJet al., 2019,

    Redox-switchable α-diimine palladium catalysts for control of polyethylene topology

    , Polymer, Vol: 179, ISSN: 0032-3861

    A 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 paper
    Boyle J, Seneviratne A, Han Y, Jiang L, Walter E, Cave L, Shaikh A, Long NJ, Carling D, Mason JC, Haskard DOet 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 article
    Wang L, Long NJ, Li L, Lu Y, Li M, Cao J, Zhang Y, Zhang Q, Xu S, Yang Z, Mao C, Peng Met 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 article
    Miller 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: 1359-7345

    The 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)].

  • Journal article
    Mann PB, Afzal K, Long NJ, Thanou M, Green Met al., 2019,

    A glassware- free combinatorial synthesis of green quantum dots using bubble wrap

    , RSC ADVANCES, Vol: 9, Pages: 16851-16855, ISSN: 2046-2069
  • Journal article
    Morse SV, Pouliopoulos AN, Chan TG, Copping MJ, Lin J, Long NJ, Choi JJet al., 2019,

    Rapid short-pulse ultrasound delivers drugs uniformly across the murine blood-brain barrier with negligible disruption

    , Radiology, Vol: 291, Pages: 459-466, ISSN: 0033-8419

    Background Previous work has demonstrated that drugs can be delivered across the blood-brain barrier by exposing circulating microbubbles to a sequence of long ultrasound pulses. Although this sequence has successfully delivered drugs to the brain, concerns remain regarding potentially harmful effects from disrupting the brain vasculature. Purpose To determine whether a low-energy, rapid, short-pulse ultrasound sequence can efficiently and safely deliver drugs to the murine brain. Materials and Methods Twenty-eight female wild-type mice underwent focused ultrasound treatment after injections of microbubbles and a labeled model drug, while three control mice were not treated (May-November 2017). The left hippocampus of 14 mice was exposed to low-energy short pulses (1 MHz; five cycles; peak negative pressure, 0.35 MPa) of ultrasound emitted at a rapid rate (1.25 kHz) in bursts (0.5 Hz), and another 14 mice were exposed to standard long pulses (10 msec, 0.5 Hz) containing 150 times more acoustic energy. Mice were humanely killed at 0 (n = 5), 10 (n = 3), or 20 minutes (n = 3) after ultrasound treatment. Hematoxylin-eosin (H-E) staining was performed on three mice. The delivered drug dose and distribution were quantified with the normalized optical density and coefficient of variation. Safety was assessed by H-E staining, the amount of albumin released, and the duration of permeability change in the blood-brain barrier. Statistical analysis was performed by using the Student t test. Results The rapid short-pulse sequence delivered drugs uniformly throughout the parenchyma. The acoustic energy emitted from the microbubbles also predicted the delivered dose (r = 0.97). Disruption in the blood-brain barrier lasted less than 10 minutes and 3.4-fold less albumin was released into the brain than with long pulses. No vascular or tissue damage from rapid short-pulse exposure was observable using H-E staining. Conclusion The rapid short-pulse ultrasound sequence is a minimally

  • Journal article
    Hernandez-Gil J, Braga M, Harriss B, Carroll LS, Leow CH, Tang M-X, Aboagye EO, Long NJet al., 2019,

    Development of Ga-68-labelled ultrasound microbubbles for whole-body PET imaging

    , Chemical Science, Vol: 10, Pages: 5603-5615, ISSN: 2041-6520

    Microbubble (MB) contrast agents have revolutionalised the way ultrasound (US) imaging can be used clinically and pre-clinically. Contrast-enhanced US offers improvements in soft-tissue contrast, as well as the ability to visualise disease processes at the molecular level. However, its inability to provide in vivo whole-body imaging can hamper the development of new MB formulations. Herein, we describe a fast and efficient method for achieving 68Ga-labelling of MBs after a direct comparison of two different strategies. The optimised approach produces 68Ga-labelled MBs in good yields through the bioorthogonal inverse-electron-demand Diel–Alder reaction between a trans-cyclooctene-modified phospholipid and a new tetrazine-bearing HBED-CC chelator. The ability to noninvasively study the whole-body distribution of 68Ga-labelled MBs was demonstrated in vivo using positron emission tomography (PET). This method could be broadly applicable to other phospholipid-based formulations, providing accessible solutions for in vivo tracking of MBs.

  • Journal article
    Leow CH, Bush N, Stanziola A, Braga M, Shah A, Hernández-Gil J, Long NJ, Aboagye E, Bamber J, Tang Met al., 2019,

    3D microvascular imaging using high frame rate ultrasound and ASAP without contrast agents: development and initial in vivo evaluation on non-tumour and tumour models

    , IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control, Vol: 66, Pages: 939-948, ISSN: 0885-3010

    Three-dimensional imaging is valuable to non-invasively assess angiogenesis given the complex 3D architecture of vascular networks. The emergence of high frame rate (HFR) ultrasound, which can produce thousands of images per second, has inspired novel signal processing techniques and their applications in structural and functionalimaging of blood vessels. Although highly sensitive vascular mapping has been demonstrated using ultrafast Doppler, the detectability of microvasculature from the background noise may be hindered by the low signal to noise ratio (SNR) particularly in deeper region and without the use of contrast agents. We have recently demonstrated a coherence based technique, acoustic sub-aperture imaging (ASAP), for super-contrast vascular imaging and illustrated the contrast improvement using HFR contrast-enhanced ultrasound. In this work, we provide a feasibility study for microvascular imaging using ASAP without contrast agents, and extend its capability from 2D to volumetric vascular mapping. Using an ultrasound research system and a pre-clinical probe, we demonstrated the improved visibility of microvascular mapping using ASAP in comparison to ultrafast Power Doppler (PD) on a mouse kidney, liver and tumour without contrast agent injection. The SNR of ASAP images improves in average by 10dB when compared to PD. Besides, directional velocity mappings were also demonstrated by combining ASAP with the phase information extracted from lag-1 autocorrelation. Three-dimensional vascular and velocity mapping of the mouse kidney, liver and tumour were demonstrated by stackingthe ASAP images acquired using 2D ultrasound imaging and a trigger-controlled linear translation stage. The 3D results depicted clear micro-vasculature morphologies and function

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