9 research outputs found
Investigations into the Radiochemistry of Gallium- and Fluorine-Containing Compounds for Molecular Imaging Applications
Applications of âHotâ and âColdâ Bis(thiosemicarbazonato) Metal Complexes in Multimodal Imaging
Synthesis, radiolabelling and in vitro imaging of multifunctional nanoceramics
Molecular imaging has become a powerful technique in preclinical and clinical research aiming towards the diagnosis of many diseases. In this work, we address the synthetic challenges in achieving labâscale, batchâtoâbatch reproducible copperâ64â and galliumâ68âradiolabelled metal nanoparticles (MNPs) for cellular imaging purposes. Composite NPs incorporating magnetic iron oxide cores with luminescent quantum dots were simultaneously encapsulated within a thin silica shell, yielding waterâdispersible, biocompatible and luminescent NPs. Scalable surface modification protocols to attach the radioisotopes 64Cu (t1/2=12.7â
h) and 68Ga (t1/2=68â
min) in high yields are reported, and are compatible with the time frame of radiolabelling. Confocal and fluorescence lifetime imaging studies confirm the uptake of the encapsulated imaging agents and their cytoplasmic localisation in prostate cancer (PCâ3) cells. Cellular viability assays show that the biocompatibility of the system is improved when the fluorophores are encapsulated within a silica shell. The functional and biocompatible SiO2 matrix represents an ideal platform for the incorporation of 64Cu and 68Ga radioisotopes with high radiolabelling incorporation
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
Porphyrin Metalla-Assemblies Coupled to Cellulose Nanocrystals for PDT and Imaging Applications
Photodynamic therapy (PDT) is an interesting and promising approach to tackle a broad spectrum of cancer types. With the combination of a photosensitizer, light and oxygen, PDT achieves a unique selectivity by the production of localized reactive oxygen species (ROS) inside cells, which leads to their destruction. In addition, the luminescence properties of photosensitizers can be exploited to develop imaging tools. Unfortunately, the cancer selectivity and homogeneity of most photosensitizers are frequently limiting the performances of PDT and cancer detection/characterization by luminescence imaging. Consequently, our study aims to use cellulose nanocrystals to transport and deliver radiolabeled photo-responsive metalla-assemblies to create a new generation of theranostic agents for PDT and imaging applications. The synthesis, structural characterization, cytotoxicity evaluation, and in vivo biodistribution imaging of the compounds are presented. The best candidates show excellent biological activity and selectivity towards ovarian carcinoma cell line (A2780), cisplatin resistant ovarian carcinoma cell line (A2780cis) versus normal human embryonic kidney cells (HEK293T), as well as efficient imaging properties, suggesting a potential use as multimodal theranostic agents
Optical to Planar X-ray Mouse Image Mapping in Preclinical Nuclear Medicine Using Conditional Adversarial Networks
In the current work, a pix2pix conditional generative adversarial network has been evaluated as a potential solution for generating adequately accurate synthesized morphological X-ray images by translating standard photographic images of mice. Such an approach will benefit 2D functional molecular imaging techniques, such as planar radioisotope and/or fluorescence/bioluminescence imaging, by providing high-resolution information for anatomical mapping, but not for diagnosis, using conventional photographic sensors. Planar functional imaging offers an efficient alternative to biodistribution ex vivo studies and/or 3D high-end molecular imaging systems since it can be effectively used to track new tracers and study the accumulation from zero point in time post-injection. The superimposition of functional information with an artificially produced X-ray image may enhance overall image information in such systems without added complexity and cost. The network has been trained in 700 input (photography)/ground truth (X-ray) paired mouse images and evaluated using a test dataset composed of 80 photographic images and 80 ground truth X-ray images. Performance metrics such as peak signal-to-noise ratio (PSNR), structural similarity index measure (SSIM) and Fréchet inception distance (FID) were used to quantitatively evaluate the proposed approach in the acquired dataset
Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting
The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111. The radiolabeling process yielded >95% with a molar activity of 10 MBq/nmol and a radiochemical purity of >98%. Stability studies have shown a remarkable resistance to degradation (>93%) within 120 h of incubation in human blood. The in vitro uptake of [111In]In-IP-001 was assessed for up to 24 h on a high CCK-2R-expressing tumor cell line (A549) showing maximal accumulation after 4 h of incubation. Biodistribution and single photon emission tomography (SPECT)/CT imaging were evaluated on BALB/c nude mice bearing A549 xenograft tumors. Implanted tumors could be clearly visualized after only 4 h post injection (2.36 \ub1 0.26% ID/cc), although a high amount of radiotracer was also found in the liver, kidneys, and spleen (8.25 \ub1 2.21%, 6.99 \ub1 0.97%, and 3.88 \ub1 0.36% ID/cc, respectively). Clearance was slow by both hepatobiliary and renal excretion. Tumor retention persisted for up to 24 h, with the tumor to organs ratio increasing over-time and ending with a tumor uptake (1.52 \ub1 0.71% ID/cc) comparable to liver and kidneys
Transforming the chemical structure and bio-nano activity of doxorubicin by ultrasound for selective killing of cancer cells
Reconfiguring the structure and selectivity of existing chemotherapeutics represents an opportunity for developing novel tumor-selective drugs. Here, as a proof-of-concept, the use of high-frequency sound waves is demonstrated to transform the nonselective anthracycline doxorubicin into a tumor selective drug molecule. The transformed drug self-aggregates in water to form approximate to 200 nm nanodrugs without requiring organic solvents, chemical agents, or surfactants. The nanodrugs preferentially interact with lipid rafts in the mitochondria of cancer cells. The mitochondrial localization of the nanodrugs plays a key role in inducing reactive oxygen species mediated selective death of breast cancer, colorectal carcinoma, ovarian carcinoma, and drug-resistant cell lines. Only marginal cytotoxicity (80-100% cell viability) toward fibroblasts and cardiomyocytes is observed, even after administration of high doses of the nanodrug (25-40 mu g mL(-1)). Penetration, cytotoxicity, and selectivity of the nanodrugs in tumor-mimicking tissues are validated by using a 3D coculture of cancer and healthy cells and 3D cell-collagen constructs in a perfusion bioreactor. The nanodrugs exhibit tropism for lung and limited accumulation in the liver and spleen, as suggested by in vivo biodistribution studies. The results highlight the potential of this approach to transform the structure and bioactivity of anticancer drugs and antibiotics bearing sono-active moieties
Synthesis, Radiolabelling and In Vitro Imaging of Multifunctional Nanoceramics
[EN] Molecular imaging has become a powerful technique in preclinical and clinical research aiming towards the diagnosis of many diseases. In this work, we address the synthetic challenges in achieving lab-scale, batch-to-batch reproducible copper-64- and gallium-68-radiolabelled metal nanoparticles (MNPs) for cellular imaging purposes. Composite NPs incorporating magnetic iron oxide cores with luminescent quantum dots were simultaneously encapsulated within a thin silica shell, yielding water-dispersible, biocompatible and luminescent NPs. Scalable surface modification protocols to attach the radioisotopes Cu (t=12.7 h) and Ga (t=68 min) in high yields are reported, and are compatible with the time frame of radiolabelling. Confocal and fluorescence lifetime imaging studies confirm the uptake of the encapsulated imaging agents and their cytoplasmic localisation in prostate cancer (PC-3) cells. Cellular viability assays show that the biocompatibility of the system is improved when the fluorophores are encapsulated within a silica shell. The functional and biocompatible SiO matrix represents an ideal platform for the incorporation of Cu and Ga radioisotopes with high radiolabelling incorporation.The authors are grateful for the helpful contributions, discussions and training received from the following: Professors Jason Lewis, Stephen Faulkner, and Philip Blower (MSKCC New York, Oxford and London KCL, respectively) and Drs H. Betts and P. Waghorn (Oxford and Harvard, respectively). The authors would like to thank Drs Paul Burke and Patrick Riss (Wolfson Brain Imaging Centre, Addenbrookeâs Hospital, Cambridge) for provision of 64Cu and training in this facility. Dr. Adrian T. Rogers (Microscopy and Analysis Suite), Prof. Rex M. Tyrrell (Department of Pharmacy & Pharmacology at the University of Bath), Rebecca Diment (Bath), Dan Lee (Oxford), Drs Justin P. OâByrne and Stephen E. Flower are thanked for their invaluable contribution to preliminary aspects of this work. We thank Dr Michael W. Jones (Oxford) for assistance with the acquisition of some of the fluorescence microscopy images, Professor Quentin Pankhurst (UCL) for assistance with magnetic measurements and Dr N. Rees (Oxford) for paramagnetic NMR work. Dr Petra Cameron is thanked for assistance with early-stage tests on a proof-of-principle quantum dot encapsulation. The authors thank the Royal Society, TSB, EPSRC and MRC for funding, also the EPSRC Mass Spectrometry service (Swansea). The team was also funded by the European Commission FP7 Programme through the Marie Curie Initial Training Network PROSENSE (grant no. 317420, 2012â2016) and SIP also thanks the European Commission for an ERC Consolidator Grant (O2SENSE Program 617107, 2014â2019)