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Find video protocols related to scientific articles indexed in Pubmed.
(64)Cu-labeled LyP-1-dendrimer for PET-CT imaging of atherosclerotic plaque.
Bioconjug. Chem.
PUBLISHED: 01-31-2014
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The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [(18)F]FBA-LyP-1 was low (0.31 ± 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with (64)Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE(-/-)) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-(64)Cu than the (ARAL)4-dendrimer-(64)Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-(64)Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-(64)Cu (0.22 ± 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in vivo PET imaging of plaque and that LyP-1 could be further exploited for the delivery of therapeutics with multivalent carriers or nanoparticles.
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AETIQ: a novel synthetic compound with anti-inflammatory properties in activated microglia.
Inflammation
PUBLISHED: 01-10-2014
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Neuroinflammation is believed to be involved in the pathogenesis of neurodegenerative diseases. Our novel synthetic compound 2-acetyl-1-ethyl-7-hydroxy-6-methoxy-1, 2, 3, 4-tetrahydroisoquinoline (AETIQ) was tested for its anti-inflammatory properties in activated microglial BV-2 cells. AETIQ attenuated nitric oxide (NO) and reactive oxygen species generation. It also downregulated the production of the proinflammatory enzymes inducible NO synthase, cyclooxygenase-2, and matrix metalloproteinase-3 at both mRNA and protein levels. Furthermore, AETIQ suppressed generation of the proinflammatory cytokines IL-1? and TNF-? as determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and ELISA assays. AETIQ attenuated NF?B signaling by downregulating NF?B nuclear translocation. The compound was stable against the liver enzymes in the microsomal and S9 fractions, indicative of good bioavailability. These results suggested that AETIQ might be utilized towards development of a therapy for neuroinflammation-related diseases.
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The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis.
Nat Commun
PUBLISHED: 08-10-2013
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MicroRNAs (miRNAs) regulate cardiovascular biology and disease, but the role of flow-sensitive microRNAs in atherosclerosis is still unclear. Here we identify miRNA-712 (miR-712) as a mechanosensitive miRNA upregulated by disturbed flow (d-flow) in endothelial cells, in vitro and in vivo. We also show that miR-712 is derived from an unexpected source, pre-ribosomal RNA, in an exoribonuclease-dependent but DiGeorge syndrome critical region 8 (DGCR8)-independent manner, suggesting that it is an atypical miRNA. Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase 3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) and stimulate pro-atherogenic responses, endothelial inflammation and permeability. Furthermore, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis. Finally, we report that human miR-205 shares the same seed sequence as murine-specific miR-712 and also targets TIMP3 in a flow-dependent manner. Targeting these mechanosensitive athero-miRs may provide a new treatment paradigm in atherosclerosis.
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A phantom for visualization of three-dimensional drug release by ultrasound-induced mild hyperthermia.
Med Phys
PUBLISHED: 08-10-2013
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Ultrasound-induced mild hyperthermia has advantages for noninvasive, localized and controlled drug delivery. In this study, a tissue-mimicking agarose-based phantom with a thermally sensitive indicator was developed for studying the spatial drug delivery profile using ultrasound-induced mild hyperthermia.
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A comparison of image contrast with (64)Cu-labeled long circulating liposomes and (18)F-FDG in a murine model of mammary carcinoma.
Am J Nucl Med Mol Imaging
PUBLISHED: 01-05-2013
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Conjugation of the (64)Cu PET radioisotope (t(1/2) = 12.7 hours) to long circulating liposomes enables long term liposome tracking. To evaluate the potential clinical utility of this radiotracer in diagnosis and therapeutic guidance, we compare image contrast, tumor volume, and biodistribution of (64)Cu-liposomes to metrics obtained with the dominant clinical tracer, (18)F-FDG. Twenty four female FVB mice with MET1 mammary carcinoma tumor grafts were examined. First, serial PET images were obtained with the (18)F-FDG radiotracer at 0.5 hours after injection and with the (64)Cu-liposome radiotracer at 6, 18, 24, and 48 hours after injection (n = 8). Next, paired imaging and histology were obtained at four time points: 0.5 hours after (18)F-FDG injection and 6, 24, and 48 hours after (64)Cu-liposome injection (n = 16). Tissue biodistribution was assessed with gamma counting following necropsy and tumors were paraffin embedded, sectioned, and stained with hematoxylin and eosin. The contrast ratio of images obtained using (18)F-FDG was 0.88 ± 0.01 (0.5 hours after injection), whereas with the (64)Cu-liposome radiotracer the contrast ratio was 0.78 ± 0.01, 0.89 ± 0.01, 0.88 ± 0.01, and 0.94 ± 0.01 at 6, 18, 24, and 48 hours, respectively. Estimates of tumor diameter were comparable between (64)Cu-liposomes and (18)F-FDG, (64)Cu-liposomes and necropsy, and (64)Cu-liposomes and ultrasound with Pearsons r-squared values of 0.79, 0.79, and 0.80, respectively. Heterogeneity of tumor tracer uptake was observed with both tracers, correlating with regions of necrosis on histology. The average tumor volume of 0.41 ± 0.05 cc measured with (64)Cu-liposomes was larger than that estimated with (18)F-FDG (0.28 ± 0.04 cc), with this difference apparently resulting primarily from accumulation of the radiolabeled particles in the pro-angiogenic tumor rim. The imaging of radiolabeled nanoparticles can facilitate tumor detection, identification of tumor margins, therapeutic evaluation and interventional guidance.
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Novel method to label solid lipid nanoparticles with 64cu for positron emission tomography imaging.
Bioconjug. Chem.
PUBLISHED: 03-09-2011
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Solid lipid nanoparticles (SLNs) are submicrometer (1-1000 nm) colloidal carriers developed in the past decade as an alternative system to traditional carriers (emulsions, liposomes, and polymeric nanoparticles) for intravenous applications. Because of their potential as drug carriers, there is much interest in understanding the in vivo biodistribution of SLNs following intravenous (i.v.) injection. Positron emission tomography (PET) is an attractive method for investigating biodistribution but requires a radiolabeled compound. In this work, we describe a method to radiolabel SLN for in vivo PET studies. A copper specific chelator, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N,N,N-tetraacetic acid (BAT), conjugated with a synthetic lipid, was incorporated into the SLN. Following incubation with (64)CuCl(2) for 1 h at 25 °C in 0.1 M NH(4)OAc buffer (pH 5.5), the SLNs (?150 nm) were successfully radiolabeled with (64)Cu (66.5% radiolabeling yield), exhibiting >95% radiolabeled particles following purification. The (64)Cu-SLNs were delivered intravenously to mice and imaged with PET at 0.5, 3, 20, and 48 h post injection. Gamma counting was utilized post imaging to confirm organ distributions. Tissue radioactivity (% injected dose/gram, %ID/g), obtained by quantitative analysis of the images, suggests that the (64)Cu-SLNs are circulating in the bloodstream after 3 h (blood half-life ?1.4 h), but are almost entirely cleared by 48 h. PET and gamma counting demonstrate that approximately 5-7%ID/g (64)Cu-SLNs remain in the liver at 48 h post injection. Stability assays confirm that copper remains associated with the SLN over the 48 h time period and that the biodistribution patterns observed are not from free, dissociated copper. Our results indicate that SLNs can be radiolabeled with (64)Cu, and their biodistribution can be quantitatively evaluated by in vivo PET imaging and ex vivo gamma counting.
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Positron emission tomography imaging of the stability of Cu-64 labeled dipalmitoyl and distearoyl lipids in liposomes.
J Control Release
PUBLISHED: 01-05-2011
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Changes in lipid acyl chain length can result in desorption of lipid from the liposomal anchorage and interaction with blood components. PET studies of the stability of such lipids have not been performed previously although such studies can map the pharmacokinetics of unstable lipids non-invasively in vivo. The purpose of this study was to characterize the in vivo clearance of (64)Cu-labeled distearoyl- and dipalmitoyl lipid included within long circulating liposomes. Distearoyl and dipalmitoyl maleimide lipids (1mol%) in liposomes were labeled with a (64)Cu-incorporated bifunctional chelator (TETA-PDP) after the activation of pyridine disulfide to thiol by TCEP. Long circulating liposomes containing HSPC:DSPE-PEG2k-OMe:cholesterol: x (55:5:39:1), where x was (64)Cu-DSPE or (64)Cu-DPPE, or HSPC:DSPE-PEG2k-OMe:cholesterol:(64)Cu-DSPE:DPPC (54:5:39:1:1) were evaluated in serum (in vitro) and via intravenous injection to FVB mice. The time-activity curves for the blood, liver, and kidney were measured from PET images and the biodistribution was performed at 48h. In vitro assays showed that (64)Cu-DPPE transferred from liposomes to serum with a 7.9h half-life but (64)Cu-DSPE remained associated with the liposomes. The half clearance of radioactivity from the blood pool was 18 and 5h for (64)Cu-DSPE- and (64)Cu-DPPE liposome-injected mice, respectively. The clearance of radioactivity from the liver and kidney was significantly greater following the injection of (64)Cu-DPPE-labeled liposomes than (64)Cu-DSPE-labeled liposomes at 6, 18 and 28h. Forty eight hours after injection, the whole body radioactivity was 57 and 17% ID/cc for (64)Cu-DSPE and (64)Cu-DPPE, respectively. These findings suggest that the acyl chain length of the radiolabel should be considered for liposomal PET studies and that PET is an effective tool for evaluating the stability of nanoformulations in vivo.
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Copper-doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity.
Mol. Pharm.
PUBLISHED: 10-08-2010
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Repeated administration of chemotherapeutics is typically required for the effective treatment of highly aggressive tumors and often results in systemic toxicity. We have created a copper-doxorubicin complex within the core of liposomes and applied the resulting particle in multidose therapy. Copper and doxorubicin concentrations in the blood pool were similar at 24 h (?40% of the injected dose), indicating stable circulation of the complex. Highly quenched doxorubicin fluorescence remained in the blood pool over tens of hours, with fluorescence increasing only with the combination of liposome disruption and copper trans-chelation. At 48 h after injection, doxorubicin fluorescence within the heart and skin was one-fifth and one-half, respectively, of fluorescence observed with ammonium sulfate-loaded doxorubicin liposomes. After 28 days of twice per week doxorubicin administration of 6 mg/kg, systemic toxicity (cardiac hypertrophy and weight and hair loss) was not detected with the copper-doxorubicin liposomes but was substantial with ammonium sulfate-loaded doxorubicin liposomes. We then incorporated two strategies designed to enhance efficacy, mTOR inhibition (rapamycin) to slow proliferation and therapeutic ultrasound to enhance accumulation and local diffusion. Tumor accumulation was ?10% ID/g and was enhanced approximately 2-fold with the addition of therapeutic ultrasound. After the 28-day course of therapy, syngeneic tumors regressed to a premalignant phenotype of ?(1 mm)(3) or could not be detected.
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Liposomal Cu-64 labeling method using bifunctional chelators: poly(ethylene glycol) spacer and chelator effects.
Bioconjug. Chem.
PUBLISHED: 06-24-2010
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Two bifunctional Cu-64 chelators (BFCs), (6-(6-(3-(2-pyridyldithio)propionamido)hexanamido)benzyl)-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA-PDP) and 4-(2-(2-pyridyldithioethyl)ethanamido)-11-carboxymethyl-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A-PDEA), were synthesized and conjugated to long-circulating liposomes (LCLs) via attachment to a maleimide lipid. An in vitro stability assay of (64)Cu-TETA, (64)Cu-TETA-PEG2k, and (64)Cu-CB-TE2A-PEG2k liposomes showed that more than 86% of the radioactivity remains associated with the liposomal fraction after 48 h of incubation with mouse serum. The in vivo time activity curves (TAC) for the three liposomal formulations showed that approximately 50% of the radioactivity cleared from the blood pool in 16-18 h. As expected, the in vivo biodistribution and TAC data obtained at 48 h demonstrate that the clearance of radioactivity from the liver slows with the incorporation of a poly(ethylene glycol)-2k (PEG2k) brush. Our data suggest that (64)Cu-TETA and (64)Cu-CB-TE2A are similarly stable in the blood pool and accumulation of radioactivity in the liver and spleen is not related to the stability of Cu-64 chelator complex; however, clearance of Cu-64 from the liver and spleen are faster when injected as (64)Cu-TETA-chelated liposomes rather than (64)Cu-CB-TE2A-chelated liposomes.
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Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors.
Cancer Res.
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Acquisition of the epithelial-mesenchymal transition (EMT) tumor phenotype is associated with impaired chemotherapeutic delivery and a poor prognosis. In this study, we investigated the application of therapeutic ultrasound methods available in the clinic to increase nanotherapeutic particle accumulation in epithelial and EMT tumors by labeling particles with a positron emission tomography tracer. Epithelial tumors were highly vascularized with tight cell-cell junctions, compared with EMT tumors where cells displayed an irregular, elongated shape with loosened cell-cell adhesions and a reduction in E-cadherin and cytokeratins 8/18 and 19. Without ultrasound, the accumulation of liposomal nanoparticles administered to tumors in vivo was approximately 1.5 times greater in epithelial tumors than EMT tumors. When ultrasound was applied, both nanoaccumulation and apparent tumor permeability were increased in both settings. Notably, ultrasound effects differed with thermal and mechanical indices, such that increasing the thermal ultrasound dose increased nanoaccumulation in EMT tumors. Taken together, our results illustrate how ultrasound can be used to enhance nanoparticle accumulation in tumors by reducing their intratumoral pressure and increasing their vascular permeability.
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Comparison of PET Imaging with (64)Cu-Liposomes and (18)F-FDG in the 7,12-Dimethylbenz[a]anthracene (DMBA)-Induced Hamster Buccal Pouch Model of Oral Dysplasia and Squamous Cell Carcinoma.
Mol Imaging Biol
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Currently, 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) is the gold standard radiotracer for staging of head and neck cancer; however, the low sensitivity of this tracer can impede detection of early lesions. (64)Cu-liposomes accumulate in various cancers and provide both a sensitive tracer and an indication of the biodistribution of nanotherapeutics. Here, the accumulation of (64)Cu-liposomes in early and established cancers is assessed and compared with (18)F-FDG in a head and neck cancer model.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.