Publications
306 results found
Wang C, Sun W, Zhang J, et al., 2021, An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy, NATURE BIOMEDICAL ENGINEERING, Vol: 5, Pages: 278-289, ISSN: 2157-846X
- Author Web Link
- Cite
- Citations: 1
Ismael A, Al-Jobory A, Wang X, et al., 2021, Molecular-scale thermoelectricity: as simple as 'ABC' (vol 2, pg 5329, 2020), NANOSCALE ADVANCES, Vol: 3, Pages: 619-619, ISSN: 2516-0230
Blower PJ, Cusnir R, Darwesh A, et al., 2021, Gallium: New developments and applications in radiopharmaceutics, RECENT HIGHLIGHTS I, Editors: Hubbard, VanEldik, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 1-35
- Author Web Link
- Cite
- Citations: 4
Boyle J, Long NJ, Walter ERH, et al., 2020, COMPOUNDS FOR THE DETECTION OF HEME OXYGENASE 1 (HO-1), AND METHODS AND USES INVOLVING THE SAME, 2017871.1
The present invention relates to compounds for the detection of heme oxygenase 1 (HO-1), in particular porphyrin, chlorin, bacteriochlorin or isobacteriochlorin compounds having a tetrapyrrole or reduced tetrapyrrole backbone and a fluorophore. Such compounds can be used in the detection of HO-1 in vivo, ex vivo and in vitro, and can also be used in methods of diagnosis and as research reagents.
Ismael A, Al-Jobory A, Wang X, et al., 2020, Molecular-scale thermoelectricity: as simple as 'ABC', NANOSCALE ADVANCES, Vol: 2, Pages: 5329-5334, ISSN: 2516-0230
- Author Web Link
- Cite
- Citations: 12
Morse SV, Boltersdorf T, Chan TG, et al., 2020, In vivo delivery of a fluorescent FPR2/ALX-targeted probe using focused ultrasound and microbubbles to image activated microglia, RSC Chemical Biology, Vol: 1, Pages: 385-389, ISSN: 2633-0679
To image activated microglia, a small-molecule FPR2/ALX-targeted fluorescent probe was locally delivered into the brain using focused ultrasound and microbubbles. The probe did not co-localise with neurons or astrocytes but accumulated in activated microglia, making this a potential imaging tool for future drug discovery programs focused on neurological disorders.
Seneviratne A, Han Y, Wong E, et al., 2020, Hematoma resolution in vivo is directed by Activating Transcription Factor 1, Circulation Research, Vol: 127, Pages: 928-944, ISSN: 0009-7330
Rationale: The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an adenosine monophosphate activated protein kinase / activating transcription factor 1 (AMPK/ATF1) pathway that directs Mhem macrophages through coregulation of heme oxygenase 1 (HMOX1, HO-1) and lipid homeostasis genes.Objective: We asked whether this pathway had an in vivo role in mice.Methods and Results: Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow derived macrophages (mBMM), heme induced HO-1, lipid regulatory genes including LXR, the growth factor IGF1, and the splenic red pulp macrophage gene Spic. This response was lost in mBMM from mice deficient in AMPK (Prkab1-/-) or ATF1 (Atf1-/-). In vivo, femoral hematomas resolved completely between day 8 and day 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1-/-) or ATF1 (Atf1-/-) (n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1-/- mice. Therefore, iron-lipid separation was Atf1-dependent.Conclusions: Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution.
Evans RJ, Lavin B, Phinikaridou A, et al., 2020, Targeted molecular iron oxide contrast agents for imaging atherosclerotic plaque, Nanotheranostics, Vol: 4, Pages: 184-194, ISSN: 2206-7418
Overview: Cardiovascular disease remains a leading cause of death worldwide, with vulnerable plaque rupture the underlying cause of many heart attacks and strokes. Much research is focused on identifying an imaging biomarker to differentiate stable and vulnerable plaque. Magnetic Resonance Imaging (MRI) is a non-ionising and non-invasive imaging modality with excellent soft tissue contrast. However, MRI has relatively low sensitivity (micromolar) for contrast agent detection compared to nuclear imaging techniques. There is also an increasing emphasis on developing MRI probes that are not based on gadolinium chelates because of increasing concerns over associated systemic toxicity and deposits1. To address the sensitivity and safety concerns of gadolinium this project focused on the development of a high relaxivity probe based on superparamagnetic iron oxide nanoparticles for the imaging of atherosclerotic plaque with MRI. With development, this may facilitate differentiating stable and vulnerable plaque in vivo.Aim: To develop a range of MRI contrast agents based on superparamagnetic iron oxide nanoparticles (SPIONs), and test them in a murine model of advanced atherosclerosis.Methods: Nanoparticles of four core sizes were synthesised by thermal decomposition and coated with poly(maleicanhydride-alt-1-octadecene) (PMAO), poly(ethyleneimine) (PEI) or alendronate, then characterised for core size, hydrodynamic size, surface potential and relaxivity. On the basis of these results, one candidate was selected for further studies. In vivo studies using 10 nm PMAO-coated SPIONs were performed in ApoE-/- mice fed a western diet and instrumented with a perivascular cuff on the left carotid artery. Control ApoE-/- mice were fed a normal chow diet and were not instrumented. Mice were scanned on a 3T MR scanner (Philips Achieva) with the novel SPION contrast agent, and an elastin-targeted gadolinium agent that was shown previously to enable visualisation of plaque burden. Histo
Cohen L, 2020, Tuning the thermoelectrical properties of anthracene-based self-assembled monolayers, Chemical Science, Vol: 11, Pages: 6836-6841, ISSN: 2041-6520
It is known that the electrical conductance of single molecules can be controlled in a deterministic manner by chemically varying their anchor groups to external electrodes. Here, by employing synthetic methodologies to vary the terminal anchor groups around aromatic anthracene cores, and by forming self-assembled monolayers (SAMs) of the resulting molecules, we demonstrate that this method of control can be translated into cross-plane SAM-on-gold molecular films. The cross-plane conductance of SAMs formed from anthracene-based molecules with four different combinations of anchors are measured to differ by a factor of approximately 3 in agreement with theoretical predictions. We also demonstrate that the Seebeck coefficient of such films can be boosted by more than an order of magnitude by an appropriate choice of anchor groups and that both positive and negative Seebeck coefficients can be realised. This demonstration that the thermoelectric properties of SAMs are controlled by their anchor groups represents a critical step towards functional ultra-thin-film devices for future molecular-scale electronics.
Long NJ, 2020, Inorganic chemistry for PET radiolabelling: <SUP>68</SUP>Ga- and <SUP>18</SUP>F-based probes for mitochondria imaging, Publisher: WILEY, Pages: 359-359, ISSN: 0362-4803
Boltersdorf 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: 1838-7640
Inflammatory 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.
Wang 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: 0002-7863
The 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.
Clough 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: 1477-9226
Global 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.
Jiang 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
Gawne 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: 1838-7640
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
Morse 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: 1838-7640
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
Smith 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
Jiang 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: 0027-8424
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.
McCluskey 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: 1535-5667
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.
Boltersdorf 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: 16764-16775
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.
Xie 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
Mundil R, Wilson LE, Schaarschmidt D, et 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.
Boyle 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
Wang 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
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)].
Mann PB, Afzal K, Long NJ, et al., 2019, A glassware- free combinatorial synthesis of green quantum dots using bubble wrap, RSC ADVANCES, Vol: 9, Pages: 16851-16855, ISSN: 2046-2069
Morse SV, Pouliopoulos AN, Chan TG, et 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
Hernandez-Gil J, Braga M, Harriss B, et 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.
Leow CH, Bush N, Stanziola A, et 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
Zhang G, Lin S, Leow CH, et al., 2019, Quantification of vaporized targeted nanodroplets using high-frame-rate ultrasound and optics, Ultrasound in Medicine and Biology, Vol: 45, Pages: 1131-1142, ISSN: 0301-5629
Owing to their ability to efficiently deliver biological cargo and sense the intracellular milieu, vertical arrays of high aspect ratio nanostructures, known as nanoneedles,are being developed as minimally invasive tools for cell manipulation. However, little is known of the mechanisms of cargo transfer across the cell membrane-nanoneedle interface. Particularly,the contributions of membrane piercing, modulation of membrane permeability and endocytosis to cargo transfer remain largelyunexplored. Here, combining state-of-the-art electron and scanning ion conductance microscopy with molecular biology techniques, we show that porous silicon nanoneedle arrays concurrently stimulate independent endocytic pathways which contribute to enhanced biomolecule delivery into human mesenchymal stem cells. Electron microscopy of the cell membrane at nanoneedle sites shows an intact lipid bilayer, accompanied by an accumulation of clathrin-coated pits and caveolae. Nanoneedles enhance the internalisation of biomolecular markers of endocytosis, highlighting the concurrent activation of caveolae-and clathrin-mediated endocytosis, alongside macropinocytosis. These events contribute to the nanoneedle-mediated delivery (nanoinjection) of nucleic acids into human stem cells, which distribute across the cytosol and the endolysosomal system. This data extends the understanding of how nanoneedles modulate biological processes to mediate interaction with the intracellular space, providing indications for the rational design of improved cell-manipulation technologies.
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.