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PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor outcome and limited therapeutic options. Imaging of IPF is limited to high-resolution computed tomography (HRCT) which is often not sufficient for a definite diagnosis and has a limited impact on therapeutic decision and patient management. Hypoxia of the lung is a significant feature of IPF but its role on disease progression remains elusive. Thus, the aim of our study was to evaluate hypoxia imaging with [18F]FMISO as a predictive biomarker of disease progression and therapy efficacy in preclinical models of lung fibrosis in comparison with [18F]FDG. METHODS: Eight-week-old C57/BL6 mice received an intratracheal administration of bleomycin (BLM) at day (D) 0 to initiate lung fibrosis. Mice received pirfenidone (300 mg/kg) or nintedanib (60 mg/kg) by daily gavage from D9 to D23. Mice underwent successive PET/CT imaging at several stages of the disease (baseline, D8/D9, D15/D16, D22/D23) with [18F]FDG and [18F]FMISO. Histological determination of the lung expression of HIF-1α and GLUT-1 was performed at D23. RESULTS: We demonstrate that mean lung density on CT as well as [18F]FDG and [18F]FMISO uptakes are upregulated in established lung fibrosis (1.4-, 2.6- and 3.2-fold increase respectively). At early stages, lung areas with [18F]FMISO uptake are still appearing normal on CT scans and correspond to areas which will deteriorate towards fibrotic lesions at later timepoints. Nintedanib and pirfenidone dramatically and rapidly decreased mean lung density on CT as well as [18F]FDG and [18F]FMISO lung uptakes (pirfenidone: 1.2-, 2.9- and 2.6-fold decrease; nintedanib: 1.2-, 2.3- and 2.5-fold decrease respectively). Early [18F]FMISO lung uptake was correlated with aggressive disease progression and better nintedanib efficacy. CONCLUSION: [18F]FMISO PET imaging is a promising tool to early detect and monitor lung fibrosis progression and therapy efficacy.
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Fluordesoxiglucose F18 , Fibrose Pulmonar Idiopática , Animais , Biomarcadores , Progressão da Doença , Humanos , Hipóxia , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Camundongos , Misonidazol/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
Dual-labeled biomolecules constitute a new generation of bioconjugates with promising applications in therapy and diagnosis. Unfortunately, the development of these new families of biologics is hampered by the technical difficulties associated with their construction. In particular, the site specificity of the conjugation is critical as the number and position of payloads can have a dramatic impact on the pharmacokinetics of the bioconjugate. Herein, we introduce dichlorotetrazine as a trivalent platform for the selective double modification of proteins on cysteine residues. This strategy is applied to the dual labeling of albumin with a macrocyclic chelator for nuclear imaging and a fluorescent probe for fluorescence imaging.
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Albumina Sérica/química , Tetrazóis/química , Aminas/química , Sequência de Aminoácidos , Animais , Cisteína/química , Corantes Fluorescentes/química , Humanos , Camundongos , Imagem Óptica , Peptídeos/química , Peptídeos/metabolismo , Albumina Sérica/metabolismo , Distribuição TecidualRESUMO
The therapeutic efficacy and adverse impacts of nanoparticles (NPs) are strongly dependent on their systemic circulation time. The corona proteins adsorbed on the NPs determine their plasma half-lives, and hence, it is crucial to identify the proteins shortening or extending their circulation time. In this work, the in vivo circulation time and corona composition of superparamagnetic iron oxide nanoparticles (SPIONs) with different surface charges/chemistries were analyzed over time. SPIONs with neutral and positive charges showed the longest and shortest circulation times, respectively. The most striking observation was that corona-coated NPs with similar opsonin/dysopsonin content showed different circulation times, implying these biomolecules are not the only contributing factors. Long-circulating NPs adsorb higher concentrations of osteopontin, lipoprotein lipase, coagulation factor VII, matrix Gla protein, secreted phosphoprotein 24, alpha-2-HS-glycoprotein, and apolipoprotein C-I, while short-circulating NPs adsorb higher amounts of hemoglobin. Therefore, these proteins may be considered to be determining factors governing the NP systemic circulation time.
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Nanopartículas , Coroa de Proteína , Tempo de Circulação Sanguínea , Coroa de Proteína/metabolismo , Nanopartículas Magnéticas de Óxido de Ferro , Proteínas SanguíneasRESUMO
CONTEXT: Old-generation photosensitizers are minimally used in current photodynamic therapy (PDT) because they absorb in the UV/blue/green region of the spectrum where biological tissues are generally highly absorbing. The UV/blue light of Cherenkov Radiation (CR) from nuclear disintegration of beta-emitter radionuclides shows promise as an internal light source to activate these photosensitizers within tissue. Outline of the study: 1) radionuclide choice and Cherenkov Radiation, 2) Photosensitizer choice, synthesis and radiolabeling, 3) CR-induced fluorescence, 4) Verification of ROS formation, 5) CR-induced PDT with either free eosine and free CR emitter, or with radiolabelled eosin. RESULTS: Cherenkov Radiation Energy Transfer (CRET) from therapeutic radionuclides (90Y) and PET imaging radionuclides (18F, 68Ga) to eosin was shown by spectrofluorimetry and in vitro, and was shown to result in a PDT process. The feasibility of CR-induced PDT (CR-PDT) was demonstrated in vitro on B16F10 murine melanoma cells mixing free eosin (λabs = 524 nm, ΦΔ 0.67) with free CR-emitter [18F]-FDG under their respective intrinsic toxicity levels (0.5 mM/8 MBq) and by trapping singlet oxygen with diphenylisobenzofuran (DPBF). An eosin-DOTAGA-chelate conjugate 1 was synthesized and radiometallated with CR-emitter [68Ga] allowed to reach 25 % cell toxicity at 0.125 mM/2 MBq, i.e. below the toxicity threshold of each component measured on controls. Incubation time was carefully examined, especially for CR emitters, in light of its toxicity, and its CR-emitting yield expected to be 3 times as much for 68Ga than 18F (considering their ß particle energy) per radionuclide decay, while its half-life is about twice as small. PERSPECTIVE: This study showed that in complete darkness, as it is at depth in tissues, PDT could proceed relying on CR emission from radionuclides only. Interestingly, this study also repurposed PET imaging radionuclides, such as 68Ga, to trigger a therapeutic event (PDT), albeit in a modest extent. Moreover, although it remains modest, such a PDT approach may be used to achieve additional tumoricidal effect to RIT treatment, where radionuclides, such as 90Y, are strong CR emitters, i.e. very potent light source for photosensitizer activation.
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Fotoquimioterapia , Fármacos Fotossensibilizantes , Animais , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Fotoquimioterapia/métodos , Radioisótopos de Gálio , Amarelo de Eosina-(YS) , RadioisótoposRESUMO
N-butyl cyanoacrylate (NBCA) is a lipophilic, permanent embolic glue that must be opacified for fluoroscopic guidance. Empirically, lipophilic Lipiodol Ultra Fluid® (LUF) has been added to produce a single-phase physically stable mixture. Varying the dilution ratio allows control of glue polymerization kinetics. LUF is far more costly than water-soluble iodinated contrast agents (ICAs). Our purpose was to evaluate whether a water-soluble nonionic iso-osmolar ICA could be used instead. We embolized both renal arteries of six swine using 1:3 NBCA-LUF or NBCA-iodixanol in 1:1, 1:3, and 1:7 ratios. We used both micro-computed tomography to assess the distality of glue penetration and indexed cast ratio and histology to assess distality, arterial obliteration, vessel-wall damage, and renal-parenchyma necrosis. Glue-LUF produced significantly greater indexed cast ratio and renal-artery ROI values and a significantly shorter cast-to-capsule distance. The injected volume was significantly greater with 1:7 iodixanol than with the other mixtures. No significant differences were found for histological evidence of artery obliteration, vessel-wall damage, or renal-parenchyma necrosis. This is the first study dealing with ICA alone as a contrast agent for cyanoacrylate embolization, compared to LUF. More research is needed to determine whether water-soluble nonionic iodinated agents can be used for human NBCA embolization given the good safety profile, availability, and low cost of ICA.
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Neurotensin receptor 1 (NTS1) is involved in the development and progression of numerous cancers, which makes it an interesting target for the development of diagnostic and therapeutic agents. A small molecule NTS1 antagonist, named [177Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers. In this study, we synthesized seven compounds based on the structure of NTS1 antagonists, bearing different chelating agents, and radiolabeled them with gallium-68 for PET imaging. These compounds were evaluated in vitro and in vivo in mice bearing a HT-29 xenograft. The compound [68Ga]Ga-bisNODAGA-16 showed a promising biodistribution profile with mainly signal in tumor (4.917 ± 0.776%ID/g, 2 h post-injection). Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS1-positive human pancreatic adenocarcinoma.
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Adamantano/análogos & derivados , Quelantes/química , Imidazóis/química , Neoplasias/diagnóstico por imagem , Compostos Radiofarmacêuticos/química , Receptores de Neurotensina/metabolismo , Adamantano/síntese química , Adamantano/química , Adamantano/farmacocinética , Animais , Linhagem Celular Tumoral , Quelantes/síntese química , Quelantes/farmacocinética , Radioisótopos de Gálio/química , Humanos , Imidazóis/síntese química , Imidazóis/farmacocinética , Camundongos , Neoplasias/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
BACKGROUND: During anthracycline treatment of cancer, there is a lack for biomarkers of cardiotoxicity besides the cardiac dysfunction. The objective of the present study was to compare [18F]FDG and [123I]MIBG (metaiodobenzylguanidine) in a longitudinal study in a doxorubicin-induced cardiotoxicity rat model. METHODS: Male Wistar Han rats were intravenously administered 3 times at 10 days' interval with saline or doxorubicin (5 mg/kg). [123I]MIBG SPECT/CT (single photon emission computed tomography-computed tomography) and simultaneous [18F]FDG PET (positron emission tomography)/7 Tesla cardiac MR (magnetic resonance) imaging acquisitions were performed at 24 h interval before first doxorubicin / saline injection and every 2 weeks during 6 weeks. At 6 weeks, the heart tissue was collected for histomorphometry measurements. RESULTS: At week 4, left ventricle (LV) end-diastolic volume was significantly reduced in the doxorubicin group. At week 6, the decreased LV end-diastolic volume was maintained, and LV end-systolic volume was increased resulting in a significant reduction of LV ejection fraction (47 ± 6% vs. 70 ± 3%). At weeks 4 and 6, but not at week 2, myocardial [18F]FDG uptake was decreased compared with the control group (respectively, 4.2 ± 0.5%ID/g and 9.2 ± 0.8%ID/g at week 6). Moreover, [18F]FDG cardiac uptake correlated with cardiac function impairment. In contrast, from week 2, a significant decrease of myocardial [123I]MIBG heart to mediastinum ratio was detected in the doxorubicin group and was maintained at weeks 4 and 6 with a 45.6% decrease at week 6. CONCLUSION: This longitudinal study precises that after doxorubicin treatment, cardiac [123I]MIBG uptake is significantly reduced as early as 2 weeks followed by the decrease of the LV end-diastolic volume and [18F]FDG uptake at 4 weeks and finally by the increase of LV end-systolic volume and decrease of LV ejection fraction at 6 weeks. Cardiac innervation imaging should thus be considered as an early key feature of anthracycline cardiac toxicity.
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PURPOSE: Molecular imaging techniques visualise biomarkers for both drug development and personalised medicine. In this field, Cherenkov luminescence imaging (CLI) seems to be very attractive by allowing imaging with clinical PET radiotracers with high-throughput capabilities. In this context, we developed a fast CLI method to detect tumour hypoxia with 18F-fluoromisonidazole (FMISO) for drug development purposes. METHODS: Colon cancer model was induced in mice by subcutaneous injection of 1 × 106 CT-26 cells. FMISO was injected, and simultaneous PET-blood oxygen level dependent (BOLD)-MRI followed by CLI were performed along with immunohistochemistry staining with pimonidazole. RESULTS: There was a significant correlation between FMISO PET and CLI tumour uptakes, consistent with the BOLD-MRI mapping. Tumour-to-background ratio was significantly higher for CLI compared with PET and MRI. Immunohistochemistry confirmed tumour hypoxia. The imaging workflow with CLI was about eight times faster than the PET-MRI procedure. CONCLUSION: CLI is a fast and relevant tool to assess tumour hypoxia. This approach could be particularly interesting for hypoxia-targeting drug development.