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Glioblastoma (GBM) is the most common and fatal primary tumor of the central nervous system (CNS) and current treatments have limited success. Chemokine signaling regulates both malignant cells and stromal cells of the tumor microenvironment (TME), constituting a potential therapeutic target against brain cancers. Here, we investigated the C–C chemokine receptor type 7 (CCR7) and the chemokine (C–C-motif) ligand 21 (CCL21) for their expression and function in human GBM and then assessed their therapeutic potential in preclinical mouse GBM models. In GBM patients, CCR7 expression positively associated with a poor survival. CCL21–CCR7 signaling was shown to regulate tumor cell migration and proliferation while also controlling tumor associated microglia/macrophage recruitment and VEGF-A production, thereby controlling vascular dysmorphia. Inhibition of CCL21–CCR7 signaling led to an increased sensitivity to temozolomide-induced tumor cell death. Collectively, our data indicate that drug targeting of CCL21–CCR7 signaling in tumor and TME cells is a therapeutic option against GBM. [ABSTRACT FROM AUTHOR]

Objective: Assessment of lung development and maturity is of utmost importance in prenatal counseling. Blood oxygen level-dependent (BOLD) effect MRI was developed for functional evaluations of organs. To date, no data are available in fetal lungs and nothing is known about the existence of a BOLD effect in the lungs. The aim of our study was to evaluate if a BOLD response could be detected in fetal lungs.Materials and Methods: From January 2014 to December 2016, 38 healthy pregnant women were prospectively enrolled. After a routine scan on a 1.5-T MRI device (normoxic period), maternal hyperoxia was induced for 5 min before the BOLD sequence (hyperoxic period). R2* was evaluated by fitting average intensity of the signal, both for normoxic (norm) and hyperoxic (hyper) periods.Results: A significant BOLD response was observed after maternal hyperoxia in the lungs with a mean R2* decrease of 12.1 ± 2.5% (p < 0.001), in line with the placenta response with a mean R2* decrease of 19.2 ± 5.9% (p < 0.0001), confirming appropriate oxygen uptake. Conversely, no significant BOLD effect was observed for the brain nor the liver with a mean ∆R2* of 3.6 ± 3.1% (p = 0.64) and 2.8 ± 3.7% (p = 0.23).Conclusion: This study shows for the first time in human that a BOLD response can be observed in the normal fetal lung despite its prenatal "non-functional status." If confirmed in congenital lung and chest malformations, this property could be used in addition to the lung volume for a better prediction of postnatal respiratory status.Key Points: • Blood oxygen level-dependent (BOLD) effect MRI was developed for functional evaluations of organs and could have interesting implications for the fetal organs. • Assessment of lung development is of utmost importance in prenatal counseling, but to date no data are available in fetal lungs. • BOLD response can be observed in the normal fetal lung opening the way to studies on fetus with pathological lungs. [ABSTRACT FROM AUTHOR]

Purpose: Physiological motion and partial volume effect (PVE) significantly degrade the quality of cardiac positron emission tomography (PET) images in the fast-beating hearts of rodents. Several Super-resolution (SR) techniques using a priori anatomical information have been proposed to correct motion and PVE in PET images. Ultrasound is ideally suited to capture real-time high-resolution cine images of rodent hearts. Here, we evaluated an ultrasound-based SR method using simultaneously acquired and co-registered PET-CT-Ultrafast Ultrasound Imaging (UUI) of the beating heart in closed-chest rodents. Procedures: The method was tested with numerical and animal data (n = 2) acquired with the non-invasive hybrid imaging system PETRUS that acquires simultaneously PET, CT, and UUI. Results: We showed that ultrasound-based SR drastically enhances the quality of PET images of the beating rodent heart. For the simulations, the deviations between expected and mean reconstructed values were 2 % after applying SR. For the experimental data, when using Ultrasound-based SR correction, contrast was improved by a factor of two, signal-to-noise ratio by 11 %, and spatial resolution by 56 % (~ 0.88 mm) with respect to static PET. As a consequence, the metabolic defect following an acute cardiac ischemia was delineated with much higher anatomical precision. Conclusions: Our results provided a proof-of-concept that image quality of cardiac PET in fast-beating rodent hearts can be significantly improved by ultrasound-based SR, a portable low-cost technique. Improved PET imaging of the rodent heart may allow new explorations of physiological and pathological situations related with cardiac metabolism. [ABSTRACT FROM AUTHOR]

Background: One-anastomosis gastric bypass/mini-gastric bypass (OAGB/MGB) remains controversial because it may cause chronic biliary reflux (BR). The risk of developing esogastric cancer due to BR after OAGB/MGB is based on the results of experimental rat studies using esojejunostomy (EJ). The aim of this study was to analyze the potential long-term consequences of BR on the esogastric mucosae in OAGB/MGB-operated rats and to compare these results to those from the use of EJ. Methods: Wistar rats received OAGB/MGB (n = 16), EJ (n = 16), and sham (n = 8) operations. Mortality and weight changes were evaluated throughout the experiment. BR was measured using magnetic resonance imaging (MRI). Rats received follow-ups for 30 weeks. A double-blinded histological analysis was performed in the esogastric segments. Results: BR was diagnosed in OAGB/MGB and EJ rats using the MRI technique; no BR occurred in the sham group. After a 30-week follow-up, no incidences of dysplasia or cancer were observed in the three groups. Additionally, esophageal intestinal metaplasia and mucosal ulcerations were observed in 41.7% and 50% of EJ rats, respectively, and no incidences of these conditions were observed in OAGB/MGB and sham rats. The incidence of esophagitis was significantly higher and more severe in the EJ group compared to those in the OAGB/MGB and sham groups (EJ = 100%, OAGB/MGB = 16.7%, sham = 8.3%; p < 0.001). Conclusions: After a 30-week follow-up period, OAGB/MGB rats did not develop any precancerous or cancerous lesions when more than 40% of EJ rats had intestinal metaplasia. [ABSTRACT FROM AUTHOR]

Purpose: Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequent in patients with pheochromocytoma and paraganglioma (PPGL). They lead to SDH inactivation, mediating a massive accumulation of succinate, which constitutes a highly specific biomarker of SDHx-mutated tumors when measured in vitro. In a recent pilot study, we showed that magnetic resonance spectroscopy (1H-MRS) optimized for succinate detection (SUCCES) could detect succinate in vivo in both allografted mouse models and PPGL patients. The objective of this study was to prospectively assess the diagnostic performances of 1H-MRS SUCCES sequence for the identification of SDH deficiency in PPGL patients. Methods: Forty-nine patients presenting with 50 PPGLs were prospectively enrolled in our referral center for 1H-MRS SUCCES. Two observers blinded to the clinical characteristics and genetic status analyzed the presence of a succinate peak and confronted the results to a composite gold standard combining PPGL genetic testing and/or in vitro protein analyses in the tumor. Results: A succinate peak was observed in 20 tumors, all of which had proven SDH deficiency using the gold standard (17 patients with germline SDHx mutations, 2 with a somatic SDHD mutation, and 1 with negative SDHB IHC and SDH loss of function). A false negative result was observed in 3 tumors. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 1H-MRS SUCCES were respectively 87%, 100%, 100%, 90%, and 94%. Conclusions: Detection of succinate using 1H-MRS is a highly specific and sensitive hallmark of SDH-deficiency in PPGLs. [ABSTRACT FROM AUTHOR]

Three well-established neuroimaging markers are now included in the revised criteria for amnestic (typical) forms of Alzheimer's disease [[5]]: hippocampal atrophy assessed by MRI, temporoparietal hypometabolism shown by FDG-PET, and increased brain amyloid deposition using fibrillar amyloid PET. Can molecular PET imaging help to evidence the phenotypic diversity of Alzheimer's disease and reveal if and how the regional distribution of the pathological -amyloid and tau proteins explain the clinical expression of Alzheimer's disease? So far, amyloid PET studies of typical or atypical early-onset of Alzheimer's disease patients have shown diffuse cortical -amyloid deposits, regardless of the clinical presentation, and have not demonstrated a correlation between the cognitive profile, metabolic changes, and the distribution of the pathological protein. Importantly, the work of Sala et al. emphasizes that, although it is less specific for Alzheimer's disease than "pathophysiological" tracers (i.e., those targeting tau and amyloid), the easily accessible FDG is a powerful and efficient diagnostic tool for the diagnosis of amnestic and atypical Alzheimer's disease, even in prodromal phases. [Extracted from the article]

Productive angiogenesis, a prerequisite for tumour growth, depends on the balanced release of angiogenic and angiostatic factors by different cell types within hypoxic tumours. Natural killer (NK) cells kill cancer cells and infiltrate hypoxic tumour areas. Cellular adaptation to low oxygen is mediated by Hypoxia-inducible factors (HIFs). We found that deletion of HIF-1α in NK cells inhibited tumour growth despite impaired tumour cell killing. Tumours developing in these conditions were characterised by a high-density network of immature vessels, severe haemorrhage, increased hypoxia, and facilitated metastasis due to non-productive angiogenesis. Loss of HIF-1α in NK cells increased the bioavailability of the major angiogenic cytokine vascular endothelial growth factor (VEGF) by decreasing the infiltration of NK cells that express angiostatic soluble VEGFR-1. In summary, this identifies the hypoxic response in NK cells as an inhibitor of VEGF-driven angiogenesis, yet, this promotes tumour growth by allowing the formation of functionally improved vessels. [ABSTRACT FROM AUTHOR]

Purpose: Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy.Procedures: Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), single photon emission tomography (SPECT) with [(99m)Tc]TcO4 ([(99m)Tc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [(18)F]FDG and [(99m)Tc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel-treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed.Results: All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [(99m)Tc]TEC and [(18)F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [(18)F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [(18)F]FDG and [(99m)Tc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week(-1) in untreated, doxorubicin, and docetaxel groups, respectively.Conclusions: Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [(18)F]FDG-PET and [(99m)Tc]TEC SPECT monitor tumor response to chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Given the progress of fluorescence diffuse optical tomography (fDOT) technology, here, we study the additional benefits provided by multimodal PET/fDOT imaging by comparing the biodistribution of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) in tumors with three fluorescent probes: a glucose analog, a protease activatable optical probe, and a ligand of αvβ3 integrin.Procedures: Sequential fDOT/PET/computed tomography (CT) imaging of mice was performed with a custom multimodal mouse support that allows the subject to be transferred between the fDOT and the PET/CT scanners. Experiments were performed in xenografted tumor models derived from the human breast cancer line MDA-MB 231 and compared to ex vivo analysis.Results: The three-dimensional signals showed that the fluorescent glucose analog is not colocalized with [(18)F]FDG, raising questions about its use as a surrogate probe of the PET tracer. Fusion of [(18)F]FDG with the other fluorescent probes showed evidence of high variability both for the protease activity and the αvβ3 integrin expression during tumor growth.Conclusion: The added value of hybrid PET/fDOT over the two modalities was demonstrated for cross-validation of probes and for better characterization of tumor models. [ABSTRACT FROM AUTHOR]

Purpose: Given the progress of fluorescence diffuse optical tomography (fDOT) technology, here, we study the additional benefits provided by multimodal PET/fDOT imaging by comparing the biodistribution of 2-deoxy-2-[F]fluoro- d-glucose ([F]FDG) in tumors with three fluorescent probes: a glucose analog, a protease activatable optical probe, and a ligand of αvβ3 integrin. Procedures: Sequential fDOT/PET/computed tomography (CT) imaging of mice was performed with a custom multimodal mouse support that allows the subject to be transferred between the fDOT and the PET/CT scanners. Experiments were performed in xenografted tumor models derived from the human breast cancer line MDA-MB 231 and compared to ex vivo analysis. Results: The three-dimensional signals showed that the fluorescent glucose analog is not colocalized with [F]FDG, raising questions about its use as a surrogate probe of the PET tracer. Fusion of [F]FDG with the other fluorescent probes showed evidence of high variability both for the protease activity and the αvβ3 integrin expression during tumor growth. Conclusion: The added value of hybrid PET/fDOT over the two modalities was demonstrated for cross-validation of probes and for better characterization of tumor models. [ABSTRACT FROM AUTHOR]

Purpose: In recent years there has been an increase in the development of radioligands targeting the 18-kDa translocator protein (TSPO). TSPO expression is well documented in activated microglia and serves as a biomarker for imaging neuroinflammation. In addition, TSPO has also been reported to be overexpressed in a number of cancer cell lines and human tumours including glioma. Here we investigated the use of [F]DPA-714, a new TSPO positron emission tomography (PET) radioligand to image glioma in vivo. Methods: We studied the uptake of [F]DPA-714 in three different rat strains implanted with 9L rat glioma cells: Fischer (F), Wistar (W) and Sprague Dawley (SD) rats. Dynamic [F]DPA-714 PET imaging, kinetic modelling of PET data and in vivo displacement studies using unlabelled DPA-714 and PK11195 were performed. Validation of TSPO expression in 9L glioma cell lines and intracranial 9L gliomas were investigated using Western blotting and immunohistochemistry of brain tissue sections. Results: All rats showed significant [F]DPA-714 PET accumulation at the site of 9L tumour implantation compared to the contralateral brain hemisphere with a difference in uptake among the three strains (F > W > SD). The radiotracer showed high specificity for TSPO as demonstrated by the significant reduction of [F]DPA-714 binding in the tumour after administration of unlabelled DPA-714 or PK11195. TSPO expression was confirmed by Western blotting in 9L cells in vitro and by immunohistochemistry ex vivo. Conclusion: The TSPO radioligand [F]DPA-714 can be used for PET imaging of intracranial 9L glioma in different rat strains. This preclinical study demonstrates the feasibility of employing [F]DPA-714 as an alternative radiotracer to image human glioma. [ABSTRACT FROM AUTHOR]

Purpose: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro- N, N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4 H-pyridazino[4,5- b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects. Methods: Here we report the radiolabelling of SSR180575 with C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats. Results: The image contrast and the binding of [C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [C]PK11195. Competition studies demonstrate that [C]SSR180575 has high specific binding for the TSPO. Conclusion: [C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic. [ABSTRACT FROM AUTHOR]

Background: Many new candidate pharmaceuticals designed to improve recovery after stroke have been proposed recently, but there are still too few molecular imaging methods capable to assess their efficacy. A hallmark of the inflammatory reaction that follows focal cerebral ischemia is overexpression of the mitochondrial peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO) in the monocytic lineage and astrocytes. This overexpression can be imaged with positron emission tomography (PET) using PBR/TSPO-selective radioligands such as [(18)F]DPA-714.Purpose: Here, we tested whether PET with [(18)F]DPA-714 would evidence the effect of minocycline, a broad spectrum antibiotic presently tested as neuroprotective agent after stroke, on the inflammatory reaction induced in an experimental model of stroke.Procedures: Ten rats were subjected to a 2-h transient middle cerebral artery occlusion with reperfusion. Minocycline or saline was intravenously administrated 1 h after reperfusion and daily during the following 6 days. PET studies were performed using [(18)F]DPA-714 at 7 days after cerebral ischemia.Results: In vivo PET imaging showed a significant decrease in [(18)F]DPA-714 uptake at 7 days after cerebral ischemia in rats treated with minocycline with respect to saline-treated animals. Minocycline treatment had no effect on the size of the infarcted area.Conclusion: Minocycline administered daily during 7 days after ischemia decreases [(18)F]DPA-714 binding, suggesting that the drug exerts an anti-inflammatory activity. [(18)F]DPA-714 PET is a useful biomarker to study novel anti-inflammatory strategies in experimental cerebral ischemia. [ABSTRACT FROM AUTHOR]

We compared gene expression patterns related to cancer progression, cell adhesion and cytokine expression in v-Src-transformed isogenic cell lines with different levels of metastatic aggressiveness in syngenic animals: a high (HM) and a low metastatic (LM) cell lines, both predetermined by in vitro oncogenic transformation, and a high metastatic (NM) cell line resulting from in vivo selection of grafted LM cells. While LM and NM shared a common v-Src transforming variant different from that of HM, gene expression patterns were similar in HM and NM but different from that of LM. In this model, the induction of the metastatic phenotype by an oncogene variant or by the host environment led to highly similar expression profiles. If confirmed in other models, these results would be relevant for the diagnosis and treatment of metastasis. [ABSTRACT FROM AUTHOR]

The key role of neuroinflammation in acute and chronic neurological disorders has stimulated the search for specific radiotracers targeting the peripheral benzodiazepine receptor (PBR)/18 kDa translocator protein (TSPO), a hallmark of neuroinflammation. Here we evaluate the new radiotracer for positron emission tomography (PET) [18F]PBR111 in a rodent model of acute inflammation and compare it with [11C]CLINME, an 11C-labelled tracer of the same chemical family, and with the isoquinolinic carboxamide [11C]PK11195. We studied radiometabolites by HPLC, in vitro binding by autoradiography and in vivo brain kinetics as well as in vivo specificity of binding using PET imaging. We show that this radiotracer has a high in vitro specificity for PBR/TSPO versus central benzodiazepine receptors, as reflected by the drastic reduction of its binding to target tissue by addition of PK11195 or PBR111, while addition of flumazenil does not affect binding. Only intact [18F]PBR111 is detected in brain up to 60 min after i.v. injection, and PET imaging shows an increased uptake in the lesion as compared to the contralateral side as early as 6 min after injection. Administration of an excess of PK11195 and PBR111, 20 min after [18F]PBR111 administration, induces a rapid and complete displacement of [18F]PBR111 binding from the lesion. Modelling of the PET data using the simplified reference tissue model showed increased binding potential (BP) in comparison to [11C]PK11195. [18F]PBR111 is a metabolically stable tracer with a high specific in vitro and in vivo binding to TSPO. In addition, considering the longer half-life of 18F over 11C, these results support [18F]PBR111 as a promising PET tracer of the PBR/TSPO for neuroinflammation imaging. [ABSTRACT FROM AUTHOR]

6-[18F]Fluoro-3,4-dihydroxy- L-phenylalanine (6-[18F]F- L-DOPA) is increasingly used for PET imaging of neuroendocrine tumours. In this study, we investigated the use of 6-[18F]F- L-DOPA to detect and to monitor the progression of medullary thyroid carcinoma (MTC) in a genetically engineered mouse model of multiple endocrine neoplasia type 2A (MEN2A). Dynamic [18F]FDG and 6-[18F]F- L-DOPA small animal PET scans were acquired during 60 or 90 min in 8- to 20-month-old MEN2A transgenic mice. The kinetics of 6-[18F]F- L-DOPA, standardized uptake values (SUV) at 60 min and tumour volumes were recorded. The detection of MTCs using PET was confirmed by autopsy and histological analysis. 6-[18F]F- L-DOPA performs better than [18F]FDG for MTC detection in this transgenic mouse model. Uptake kinetics of 6-[18F]F- L-DOPA in MTCs are very different between mice but, in all cases, high contrast could be observed. Furthermore, 6-[18F]F- L-DOPA can detect tumours with sizes (1.8 mm3) that are near the resolution limit of PET, whereas they were undetectable by autopsy at the macroscopic level. 6-[18F]F- L-DOPA PET imaging can monitor the progression of MTCs in a genetically engineered mouse model. [ABSTRACT FROM AUTHOR]

The author reflects on the connection of Charles Darwin's theory of evolution with the field of molecular imaging. He cites the application of Darwin's principle of selection in the ligand molecular probe selection process. He mentions several biotechnological procedures for the selection of molecular imaging probes such as phage display, ribosome display, mRNA and bacterial display. He also notes the attractiveness of aptamers as molecular probes due to their medium molecular size.

Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benzodiazepine receptor (PBR)/translocator protein 18 kDa (TSPO) that is linked to microglial activation and considered a hallmark of neuroinflammation. The prototype positron emission tomography tracer for PBR, [11C]PK11195, has shown limitations that until now have slowed the clinical applications of PBR imaging. In recent years, dozens of new PET and SPECT radioligands for the PBR have been radiolabelled, and several have been evaluated in imaging protocols. Here we review the new PBR ligands proposed as challengers of [11C]PK11195, critically analyze preclinical imaging studies and discuss their potential as neuroinflammation imaging agents. [ABSTRACT FROM AUTHOR]

Purpose: Single-stranded minor-image oligo- nucleotides (Spiegelmers) are highly resistant to nuclease degradation and are capable of tightly and specifically binding to protein targets. Here we explored the potential of Spiegelmers as in vivo imaging probes for positron emission tomography (PET). Methods: We investigated the biodistribution and pharmacokinetics of [18F]-L-DNA and [18F]-L-RNA Spiegelmers by dynamic quantitative whole-body PET imaging after intravenous administration in non-human primates. Their metabolic profile was explored in primates and rats, and ex vivo autoradiography of [125I]-L-RNA was performed in rat kidneys, the major organ for Spiegelmer uptake. Results: Both [18F]-L-DNA and [18F]-L-RNA Spiegelmers were metabolically stable in plasma during 2 h after injection. No evidence of non-specific binding was found with either type of Spiegelmer in any tissue. Conclusion: The biodistribution and metabolic profiles of [18F]-L-DNA and [18F-L-RNA Spiegelmers highlight their potential as radiotracers for in vivo imaging applications. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the Melanoblastoma-bearing Libechov Minipigs (MeLiM) as an animal model of melanoma for in vivo imaging. Serial whole-body 2-deoxy-2-[[SUP18]F]fluoro-D-glucose positron emission tomography (FDG PET) scans were conducted on five MeLiM. In order to explore different clinical stages of the tumoural lesions, each animal was scanned two to four times, at intervals of 30-155 days. PET images were analysed by a semiquantitative method based on the tumour to muscle metabolic ratio. Histology was performed on biopsies taken between or after the scans and the histological grading of the tumours was compared with the FDG uptake. The overall sensitivity of FDG PET for the detection of cutaneous melanoma was 75%; 62.5% of involved lymph nodes were positive. Sensitivity was better for tumours with vertical growth than for flat lesions. FDG PET did not detect tumours with epidermal involvement only, nor did it detect small metastatic foci. The metabolic ratio was correlated with the evolution of the melanoma. FDG PET is effective in the staging of cutaneous melanoma and the follow-up of tumoural extension and regression in Melanoblastoma-bearing Libechov Minipigs. The results obtained in this animal model correlate well with those described in human melanoma. Accordingly, this model may be useful in testing new tracers specific for melanoma and in helping to detect molecules expressed early during tumoural regression. [ABSTRACT FROM AUTHOR]

Purpose. To compare the pharmacokinetics and bioavailability of an oligonucleotide delivered in a free form or using cationic or anionic synthetic carrier systems. Methods. Whole body dynamic quantitative imaging and metabolism of a HIV antisense oligonucleotide intravenously administered either free or incorporated into synthetic carriers were compared in baboons, using non invasive positron emission tomography and an enzyme-based competitive hybridization assay, respectively. Results. In its free form, the oligonucleotide showed high liver and kidney concentration, rapid plasmatic degradation and elimination from the body. Use of a cationic vector slightly protected the oligonucleotide against degradation and enhanced uptake by the reticulo-endothelial system. In contrast, the anionic vector dramatically enhanced the uptake in several organs, including the lungs, spleen and brain, with a prolonged accumulation of radioactivity in the brain. Using this vector, intact oligonucleotide was detected in plasma for up to two hours after injection, and the T1/2β and distribution volume increased by 4- and 7-fold, respectively. No evidence of toxicity was found after a single dose administration. Conclusions. The anionic vector improves significantly the bioavailability and the pharmacokinetics of the oligonucleotide, and is a promising delivery system for in vivo administration of therapeutic nucleic acids. [ABSTRACT FROM AUTHOR]