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We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.

The successful in vivo implementation of gene expression modulation strategies relies on effective, non-immunogenic delivery vehicles. Lipid nanoparticles are one of the most advanced non-viral clinically approved nucleic-acid delivery systems. Yet lipid nanoparticles accumulate naturally in liver cells upon intravenous administration, and hence, there is an urgent need to enhance uptake by other cell types. Here we use a conformation-sensitive targeting strategy to achieve in vivo gene silencing in a selective subset of leukocytes and show potential therapeutic applications in a murine model of colitis. In particular, by targeting the high-affinity conformation of α4β7 integrin, which is a hallmark of inflammatory gut-homing leukocytes, we silenced interferon-γ in the gut, resulting in an improved therapeutic outcome in experimental colitis. The lipid nanoparticles did not induce adverse immune activation or liver toxicity. These results suggest that our lipid nanoparticle targeting strategy might be applied for selective delivery of payloads to other conformation-sensitive targets.While targeted lipid nanoparticles might allow partial delivery of genetic materials to non-hepatic cells, the selectivity of this approach is still unsatisfying. Here the authors functionalize their lipid nanoparticles with a targeting moiety that recognizes a protein conformation specific to gut-homing leukocytes, inducing gene silencing exclusively in this cellular subset and providing a potential therapeutic strategy for inflammatory bowel disease.

Retinal neovascularization, as occurs in age-related macular degeneration, may result from an increase in VEGFA levels due to dysregulated lipid and glucose metabolism within photoreceptors. Tissues with high metabolic rates often use lipids, as well as glucose, for energy, conferring a survival advantage during feast and famine 1 . Current dogma suggests that high-energy–consuming photoreceptors depend on glucose 2 , 3 . Here we show that the retina also uses fatty acid β-oxidation for energy. Moreover, we identify a lipid sensor, free fatty acid receptor 1 (Ffar1), that curbs glucose uptake when fatty acids are available. Very-low-density lipoprotein receptor (Vldlr), which is present in photoreceptors 4 and is expressed in other tissues with a high metabolic rate, facilitates the uptake of triglyceride-derived fatty acid 5 , 6 . In the retinas of Vldlr −/− mice with low fatty acid uptake 6 but high circulating lipid levels, we found that Ffar1 suppresses expression of the glucose transporter Glut1. Impaired glucose entry into photoreceptors results in a dual (lipid and glucose) fuel shortage and a reduction in the levels of the Krebs cycle intermediate α-ketoglutarate (α-KG). Low α-KG levels promotes stabilization of hypoxia-induced factor 1a (Hif1a) and secretion of vascular endothelial growth factor A (Vegfa) by starved Vldlr −/− photoreceptors, leading to neovascularization. The aberrant vessels in the Vldlr −/− retinas, which invade normally avascular photoreceptors, are reminiscent of the vascular defects in retinal angiomatous proliferation, a subset of neovascular age-related macular degeneration (AMD) 7 , which is associated with high vitreous VEGFA levels in humans. Dysregulated lipid and glucose photoreceptor energy metabolism may therefore be a driving force in macular telangiectasia, neovascular AMD and other retinal diseases.

The immune system’s ability to recognize peptides on major histocompatibility molecules contributes to the eradication of cancers and pathogens. Tracking these responses in vivo could help evaluate the efficacy of immune interventions and improve mechanistic understanding of immune responses. For this purpose, we employ synTacs, which are dimeric major histocompatibility molecule scaffolds of defined composition. SynTacs, when labeled with positron-emitting isotopes, can noninvasively image antigen-specific CD8 + T cells in vivo. Using radiolabeled synTacs loaded with the appropriate peptides, we imaged human papillomavirus-specific CD8 + T cells by positron emission tomography in mice bearing human papillomavirus-positive tumors, as well as influenza A virus–specific CD8 + T cells in the lungs of influenza A virus–infected mice. It is thus possible to visualize antigen-specific CD8 + T-cell populations in vivo, which may serve prognostic and diagnostic roles. Antigen-specific CD8 + T cells can be imaged by immunoPET with the help of synTacs, MHC-based tools that bind to relevant T-cell receptors.

BackgroundA major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [64Cu]Cu-SARTATE to detect and monitor the disease and [67Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [64Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [67Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation.ResultsPET imaging and ex vivo biodistribution confirmed tumor uptake of [64Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [64Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [67Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [67Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064).ConclusionsClinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [64/67Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD.

Positron emission tomography combined with a specific probe presents the ability to noninvasively assess inflammatory bowel disease. We previously reported increased intestinal uptake of a 64Cu-labeled anti-β7 integrin antibody (clone FIB504.64) in colitic mice. Here, we evaluated an anti-α4β7 integrin antibody (clone DATK32), and the F(ab′)2 and Fab fragments of the anti-β7 antibody, which should have faster blood clearance than the intact antibody, as imaging probes for the detection of colitis in a mouse model.MethodsThe immunoproteins were labeled with 64Cu, injected into mice with dextran sodium sulphate-induced colitis. Positron emission tomography data were collected between 1 and 48 hours postinjection.ResultsFocal uptake of the anti-β7 fragments was observed in the gut as early as 1 hour postinjection, and they cleared more rapidly from normal tissues than the whole antibody. For example, the blood concentrations at 24 hours postinjection were 23.3 ± 3.0% ID/g for 64Cu-labeled DATK32, 12.9 ± 2.1% ID/g for FIB504.64, 4.1 ± 0.4% ID/g for FIB504.64-F(ab′)2, and 0.62 ± 0.2% ID/g for FIB504.64-Fab (P < 0.0001, analysis of variance). The ratio of uptake of DATK32 between the colitis and control groups in the large intestine (1.38) was lower than for the FIB504.64 fragments (3.15 for F(ab′)2, 1.84 for Fab) or intact FIB504.64 (1.78).ConclusionsThe lower intestinal uptake ratio of the 64Cu-labeled anti-α4β7 antibody (DATK32) compared with the anti-β7 immunoproteins suggests that targeting all β7-expressing lymphocytes, not just those expressing α4β7, is a more promising route to the development of an inflammatory bowel disease imaging agent. The FIB504.64-F(ab′)2 fragment demonstrated the greatest differential between colitis and control groups, and is therefore the most promising lead molecule for the development of an inflammatory bowel disease-specific imaging agent.

A major Utah water district reduced its energy footprint by 19% after following a two‐year energy management program, implementing both technical and organizational change in pursuit of its vision to provide a more sustainable water supply.

Acute respiratory failure can cause profound hypoxaemia that leads to organ injury or death within minutes. When conventional interventions are ineffective, the intravenous administration of oxygen can rescue patients from severe hypoxaemia, but at the risk of microvascular obstruction and of toxicity of the carrier material. Here we describe polymeric microbubbles as carriers of high volumes of oxygen (350–500 ml of oxygen per litre of foam) that are stable in storage yet quickly dissolve following intravenous injection, reverting to their soluble and excretable molecular constituents. In swine with profound hypoxaemia owing to acute and temporary (12 min) upper-airway obstruction, the microbubble-mediated delivery of oxygen led to: the maintenance of critical oxygenation, lowered burdens of cardiac arrest, improved survival, and substantially improved neurologic and kidney function in surviving animals. Our findings underscore the importance of maintaining a critical threshold of oxygenation and the promise of injectable oxygen as a viable therapy in acute and temporary hypoxaemic crises. The intravenous injection of oxygen via polymeric microbubbles that are stable in storage yet quickly dissolve following intravenous injection led to the maintenance of critical oxygenation and to improved survival in swine with profound hypoxaemia.

Since its launch in June 2006, SNM's molecular imaging Web site has grown into a powerful resource for molecular imaging professionals, referring physicians, patients and advocates, and the general public.

The dopamine D2 agonist MCL-524 is selective for the D2 receptor in the high-affinity state (D2high), and, therefore, the PET analogue, [18F]MCL-524, may facilitate the elucidation of the role of D2high in disorders such as schizophrenia. However, the previously reported synthesis of [18F]MCL-524 proved difficult to replicate and was lacking experimental details. We therefore developed a new synthesis of [18F]MCL-524 using a “non-anhydrous, minimally basic” (NAMB) approach. In this method, [18F]F− is eluted from a small (10–12 mg) trap-and-release column with tetraethylammonium tosylate (2.37 mg) in 7:3 MeCN:H2O (0.1 mL), rather than the basic carbonate or bicarbonate solution that is most often used for [18F]F− recovery. The tosylated precursor (1 mg) in 0.9 mL anhydrous acetonitrile was added directly to the eluate, without azeotropic drying, and the solution was heated (150 °C/15 min). The catechol was then deprotected with the Lewis acid In(OTf)3 (10 equiv.; 150 °C/20 min). In contrast to deprotection with protic acids, Lewis-acid-based deprotection facilitated the efficient removal of byproducts by HPLC and eliminated the need for SPE extraction prior to HPLC purification. Using the NAMB approach, [18F]MCL-524 was obtained in 5–9% RCY (decay-corrected, n = 3), confirming the utility of this improved method for the multistep synthesis of [18F]MCL-524 and suggesting that it may applicable to the synthesis of other 18F-labeled radiotracers.