RESUMO
To improve the signal-to-noise ratio of hypoxia positron emission tomography (PET) imaging, stimuli-responsive polymers are designed for the delivery of the hypoxia PET tracer fluorine-18 labeled fluoromisonidazole ([18 F]FMISO). Linear poly(N-(2-(hydroxypropyl)methacrylamide)) polymers are functionalized with hydrazide linkers that form pH-sensitive acyl hydrazone bonds after their conjugation to an [18 F]FMISO ketone analogue. The release of the [18 F]FMISO ketone analogue from the polymers is considerably faster at a lower pH and its uptake is significantly higher in cancer cells growing under acidic conditions. Additionally, the retention of the PET tracer is significantly higher in hypoxic cells compared to normoxic cells. The delivery of a PET tracer using stimuli-responsive polymers may be an attractive strategy to improve signal-to-noise ratios in PET imaging.
Assuntos
Hipóxia , Misonidazol/análogos & derivados , Tomografia por Emissão de Pósitrons , Radioisótopos de Flúor , Humanos , Concentração de Íons de Hidrogênio , Misonidazol/química , Estrutura Molecular , Razão Sinal-RuídoRESUMO
Delocalized lipophilic cations such as tri- and tetra-arylphosphonium are able to diffuse across the mitochondrial membrane, which allows them to selectively accumulate in cells with a high transmembrane potential (ΔΨm ). The mitochondrial membrane potential of cancer cells and cardiomyocytes has been reported to be significantly higher than that of normal epithelial cells. This feature can be exploited for the selective accumulation of phosphonium derivatives for the purposes of molecular imaging using radionuclides. Four structurally related Ga(III)-phosphonium salts were synthesized and fully characterized and found to be modest in toxicity toward T98G human glioblastoma cells (IC50 > 4 mM). High-activity (100 MBq) analogs containing Ga-67 were also synthesized and their stabilities in phosphate-buffered saline and human serum were determined.
Assuntos
Radioisótopos de Gálio/química , Compostos Organofosforados/química , Compostos Radiofarmacêuticos/síntese química , Linhagem Celular Tumoral , Humanos , Potencial da Membrana Mitocondrial , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Soro/efeitos dos fármacosRESUMO
Large metal-oxo clusters consistently assume spherical or regular polyhedral morphologies rather than high-aspect-ratio structures. Access to elongated core structures has now been achieved by the reaction of lanthanoid salts with a tetrazole-functionalized calixarene in the presence of a simple carboxylate co-ligand. The resulting Ln19 and Ln12 clusters are constructed from apex-fused Ln5O6 trigonal bipyramids and are formed consistently under a range of reaction conditions and reagent ratios. Altering the carboxylate co-ligand structure reliably controls the cluster length, giving access to a new class of rod-like clusters of variable length.
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Herein we describe the preparation and structure-activity relationship studies on range of stilbene based compounds and their antibacterial activity. Two related compounds, each bearing carboxylic acid moieties, exhibit good activity against several bacterial strains, including methicillin-resistant Staphylococcus aureus MRSA (ATCC 33592 and NCTC 10442). Compound 10 was most active against Moraxella catarrhalis with minimum inhibitory concentrations (MICs) of 0.12-0.25 µg mL(-1) and against Staphylococcus spp. with MICs ranging from 2-4 µg mL(-1). The derivative 17 showed increased activity with MICs of 0.06-0.25 µg mL(-1) against M. catarrhalis and 0.12-1 against Staphylococcus spp. This level of activity is similar to that reported for S. aureus for antibiotics, such as vancomycin, with MICs of ≤2.0 µg mL(-1) and clindamycin with MICs of ≤0.5 µg mL(-1). As an indicator of toxicity, 17 was tested for its ability to lyse sheep erythrocytes, and showed low haemolytic activity. Such results highlight the value of tris(stilbene) compounds as antibacterial agents providing suitable properties for further development.
Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Estilbenos/química , Animais , Ovinos , Relação Estrutura-AtividadeRESUMO
DOTA-linked glutamine analogues with a C6- alkyl and polyethyleneglycol (PEG) chain between the chelating group and the L-glutamine moiety were synthesised and labelled with 67,68Ga using established methods. High yields were achieved for the radiolabelling of the molecules with both radionuclides (>90%), although conversion of the commercially available 67Ga-citrate to the chloride species was a requirement for consistent high radiochemical yields. The generator produced 68Ga was in the [68Ga(OH)4]â» form. The 67Ga complexes and the 67Ga complexes were demonstrated to be stable in PBS buffer for a week. Uptake studies were performed with longer lived 67Ga analogues against four tumour cell lines, as well as uptake inhibition studies against L-glutamine, and two known amino acid transporter inhibitors. Marginal uptake was exhibited in the PEG variant radio-complex, and inhibition studies indicate this uptake is via a non-targeted amino acid pathway.
Assuntos
Radioisótopos de Gálio/química , Glutamina/química , Glutamina/metabolismo , Compostos Heterocíclicos com 1 Anel/química , Neoplasias/metabolismo , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Glutamina/análogos & derivados , Glutamina/síntese química , Humanos , Marcação por Isótopo , Tomografia por Emissão de Pósitrons , Traçadores Radioativos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismoRESUMO
Our aim was to report the use of 64Cu and 67Cu as a theranostic pair of radionuclides in human subjects. An additional aim was to measure whole-organ dosimetry of 64Cu and 67Cu attached to the somatostatin analog octreotate using the sarcophagine MeCOSar chelator (SARTATE) in subjects with somatostatin receptor-expressing lesions confined to the cranium, thereby permitting normal-organ dosimetry for the remainder of the body. Methods: Pretreatment PET imaging studies were performed up to 24 h after injection of [64Cu]Cu-SARTATE, and normal-organ dosimetry was estimated using OLINDA/EXM. Subsequently, the trial subjects with multifocal meningiomas were given therapeutic doses of [67Cu]Cu-SARTATE and imaged over several days using SPECT/CT. Results: Five subjects were initially recruited and imaged using PET/CT before treatment. Three of the subjects were subsequently administered 4 cycles each of [67Cu]Cu-SARTATE followed by multiple SPECT/CT imaging time points. No serious adverse events were observed, and no adverse events led to withdrawal from the study or discontinuation from treatment. The estimated mean effective dose was 3.95 × 10-2 mSv/MBq for [64Cu]Cu-SARTATE and 7.62 × 10-2 mSv/MBq for [67Cu]Cu-SARTATE. The highest estimated organ dose was in spleen, followed by kidneys, liver, adrenals, and small intestine. The matched pairing was shown by PET and SPECT intrasubject imaging to have nearly identical targeting to tumors for guiding therapy, demonstrating a potentially accurate and precise theranostic product. Conclusion: 64Cu and 67Cu show great promise as a theranostic pair of radionuclides. Further clinical studies will be required to examine the therapeutic dose required for [67Cu]Cu-SARTATE for various indications. In addition, the ability to use predictive 64Cu-based dosimetry for treatment planning with 67Cu should be further explored.
Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/diagnóstico por imagem , Meningioma/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos , Radiometria , Compostos Radiofarmacêuticos/uso terapêutico , Distribuição TecidualRESUMO
Single-crystal X-ray diffraction studies for a variety of metal ion complexes of functionalised sarcophagines (sarcophagine=sar=3,6,10,13,16,19-hexa-azabicyclo[6.6.6]icosane) have further confirmed not only that the form of the metal ion/sar unit is unique for each metal, albeit with a sensitivity of the conformation to the associated counter anions, but also that for any given metal and ligand substituent, the dimensions (bond lengths and angles) of the complex and the substituent at the secondary nitrogen centres do not differ significantly from those of the isolated components. Despite this, where the substituent contains reactive sites, the reactivity differs markedly from that of their form in an uncoordinated substrate. Rationalisations are offered for these differences, in part through the use of Hirshfeld surface analysis of the intermolecular interactions. The kinetic inertness of the complexes means that the metal ions can be considered to act as regioselective protecting groups.
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A limitation to the wider introduction of personalised dosimetry in theranostics is the relative paucity of imaging radionuclides with suitable physical and chemical properties to be paired with a long-lived therapeutic partner. As most of the beta-emitting therapeutic radionuclides emit gamma radiation as well they could potentially be used as the imaging radionuclide as well as the therapeutic radionuclide. However, the downsides are that the beta radiation will deliver a significant radiation dose as part of the treatment planning procedure, and the gamma radiation branching ratio is often quite low. Gallium-67 has been in use in nuclear medicine for over 50 years. However, the tremendous interest in gallium imaging in theranostics in recent times has focused on the PET radionuclide gallium-68. In this article it is suggested that the longer-lived gallium-67, which has desirable characteristics for imaging with the gamma camera and a suitably long half-life to match biological timescales for drug uptake and turnover, has been overlooked, in particular, for treatment planning with radionuclide therapy. Gallium-67 could also allow non-PET facilities to participate in theranostic imaging prior to treatment or for monitoring response after therapy. Gallium-67 could play a niche role in the future development of personalised medicine with theranostics.
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Various 2- and 3-thienylmethylamino-substituted cobalt(III) cage amine complexes, prepared with the objective of obtaining cage-functionalized polythienyls, have been found to be resistant to oxidative polymerization by both electrochemical and chemical procedures. X-ray structure determinations indicate that there is negligible perturbation of the physical dimensions of the thiophene moieties by the cage substituents and thus that the resistance to polymerization must be associated with the high positive charge carried by these substituents.
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A domino Horner-Wadsworth-Emmons olefination strategy has been used to prepare homologous series of (polyen)ones, and through combinatorial elaboration, corresponding families of highly branched hydrocarbons. Gas chromatography-mass spectrometry of the mixtures has enabled the rapid and unambiguous identification of several highly branched alkanes of geochemical importance. This is the first example of the use of combinatorial synthesis for the elucidation of structural connectivity.
Assuntos
Alcanos/química , Técnicas de Química Combinatória/métodos , Polipropilenos/síntese química , Cristalografia por Raios X , Cromatografia Gasosa-Espectrometria de Massas , Estrutura Molecular , Polipropilenos/químicaRESUMO
Given the strong clinical evidence that copper levels are significantly elevated in a wide spectrum of tumors, copper homeostasis is considered as an emerging target for anticancer drug design. Monitoring copper levels in vivo is therefore of paramount importance when assessing the efficacy of copper-targeting drugs. Herein, we investigated the activity of the copper-targeting compound Dextran-Catechin by developing a [64Cu]CuCl2 PET imaging protocol to monitor its effect on copper homeostasis in tumors. Methods: Protein expression of copper transporter 1 (CTR1) in tissue microarrays representing 90 neuroblastoma patient tumors was assessed by immunohistochemistry. Western blotting analysis was used to study the effect of Dextran-Catechin on the expression of CTR1 in neuroblastoma cell lines and in tumors. A preclinical human neuroblastoma xenograft model was used to study anticancer activity of Dextran-Catechin in vivo and its effect on tumor copper homeostasis. PET imaging with [64Cu]CuCl2 was performed in such preclinical neuroblastoma model to monitor alteration of copper levels in tumors during treatment. Results: CTR1 protein was found to be highly expressed in patient neuroblastoma tumors by immunohistochemistry. Treatment of neuroblastoma cell lines with Dextran-Catechin resulted in decreased levels of glutathione and in downregulation of CTR1 expression, which caused a significant decrease of intracellular copper. No changes in CTR1 expression was observed in normal human astrocytes after Dextran-Catechin treatment. In vivo studies and PET imaging analysis using the neuroblastoma preclinical model revealed elevated [64Cu]CuCl2 retention in the tumor mass. Following treatment with Dextran-Catechin, there was a significant reduction in radioactive uptake, as well as reduced tumor growth. Ex vivo analysis of tumors collected from Dextran-Catechin treated mice confirmed the reduced levels of CTR1. Interestingly, copper levels in blood were not affected by treatment, demonstrating potential tumor specificity of Dextran-Catechin activity. Conclusion: Dextran-Catechin mediates its activity by lowering CTR1 and intracellular copper levels in tumors. This finding further reveals a potential therapeutic strategy for targeting copper-dependent cancers and presents a novel PET imaging method to assess patient response to copper-targeting anticancer treatments.
Assuntos
Tomografia por Emissão de Pósitrons/métodos , Animais , Catequina , Proteínas de Transporte de Cátions , Linhagem Celular Tumoral , Cobre , Transportador de Cobre 1 , Dextranos , Feminino , Homeostase , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos BALB C , Imagem Molecular , Neuroblastoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Análise Serial de TecidosRESUMO
Physiologically stable multimodality imaging probes for positron emission tomography/single-photon emission computed tomography (PET/SPECT)-magnetic resonance imaging (MRI) were synthesized using the superparamagnetic maghemite iron oxide (γ-Fe2O3) nanoparticles (SPIONs). The SPIONs were sterically stabilized with a finely tuned mixture of diblock copolymers with either methoxypolyethylene glycol (MPEG) or primary amine NH2 end groups. The radioisotope for PET or SPECT imaging was incorporated with the SPIONs at high temperature. 57Co2+ ions with a long half-life of 270.9 days were used as a model for the radiotracer to study the kinetics of radiolabeling, characterization, and the stability of the radiolabeled SPIONs. Radioactive 67Ga3+ and Cu2+-labeled SPIONs were also produced successfully using the optimized conditions from the 57Co2+-labeling process. No free radioisotopes were detected in the aqueous phase for the radiolabeled SPIONs 1 week after dispersion in phosphate-buffered saline (PBS). All labeled SPIONs were not only well dispersed and stable under physiological conditions but also noncytotoxic in vitro. The ability to design and produce physiologically stable radiolabeled magnetic nanoparticles with a finely controlled number of functionalizable end groups on the SPIONs enables the generation of a desirable and biologically compatible multimodality PET/SPECT-MRI agent on a single T2 contrast MRI probe.
Assuntos
Coloides/química , Compostos Férricos/química , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/administração & dosagem , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Células 3T3-L1 , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dextranos/química , Ligantes , Nanopartículas de Magnetita/química , Camundongos , Mioblastos/citologia , Mioblastos/efeitos dos fármacos , Polietilenoglicóis , RatosRESUMO
[(68)Ga(DOTATATE)] has demonstrated its clinical usefulness. Both Fe(3+) and Cu(2+), potential contaminants in Gallium-68 generator eluent, substantially reduce the radiochemical (RC) yield of [(68)Ga(DOTATATE)] if the metal/ligand ratio of 1:1 is exceeded. A variety of compounds were examined for their potential ability to reduce this effect. Most had no effect on RC yield. However, addition of phosphate diminished the influence of Fe(3+) by likely forming an insoluble iron salt. Addition of ascorbic acid reduced Cu(2+) and Fe(3+) to Cu(+) and Fe(2+) respectively, both of which have limited impact on RC yields. At low ligand amounts (5 nmol DOTATATE), the addition of 30 nmol phosphate (0.19 mM) increased the tolerance of Fe(3+) from 4 nmol to 10 nmol (0.06 mM), while the addition of ascorbic acid allowed high RC yields (>95%) in the presence of 40 nmol Fe(3+) (0.25 mM) and 100 nmol Cu(2+) (0.63 mM). The effect of ascorbic acid was highly pH-dependant, and gave optimal results at pH 3.
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Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, [(68)Ga]-2, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing (68)Ga for preclinical CA IX imaging are scarce, and this is one of the first effective (68)Ga compounds reported for PET imaging of CA IX.
Assuntos
Antígenos de Neoplasias/análise , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/análise , Anidrase Carbônica IX/metabolismo , Tomografia por Emissão de Pósitrons , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Radioisótopos de Gálio , Humanos , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Nus , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
This study reports the synthesis, [(123)I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41, and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [(123)I]41 and [(123)I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [(123)I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [(131)I] therapeutic evaluation.
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Radioisótopos do Iodo/química , Radioisótopos do Iodo/uso terapêutico , Melaninas/química , Melanoma/radioterapia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
The influence of metal cations (Fe³âº, Fe²âº, In³âº, Cu²âº, Ca²âº, Al³âº, Co²âº, Lu³âº, Ni²âº, Pb²âº, Ti4âº, Y³âº, Yb³âº, Zn²âº, and Zr4âº) on the radiolabeling yield of [68Ga(DOTATATE)] was evaluated. Our most important observation was that, within our experimental limit, the metal ion/ligand ratio plays a critical role on the influence of most metal ions. More in-depth studies, with Cu²âº and Fe³âº, revealed that reaction temperature and concentration changes have little effect, but speciation changes with pH are crucial. Furthermore, we found that [68Ga(DOTATATE)] is stable in the presence of high concentrations of Fe³âº, Zn²âº and Pb²âº, but transmetalates with Cu²âº at 95°C.
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Structural studies of seven very differently functionalised derivatives of calix[4]arene have been used to provide an analysis of the numerous factors which may influence solvent adduct formation by calixarenes. Evidence is presented that even where a solvent guest is included within the calixarene cavity, interactions solely within the cavity cannot be seen as the sole influences upon the guest position and orientation.