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      1. Author :
        Chantry, A. D.; Heath, D.; Mulivor, A. W.; Pearsall, S.; Baud'huin, M.; Coulton, L.; Evans, H.; Abdul, N.; Werner, E. D.; Bouxsein, M. L.; Key, M. L.; Seehra, J.; Arnett, T. R.; Vanderkerken, K.; Croucher, P.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        J Bone Miner Res
      6. Products :
      7. Volume :
        25
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        MDA-MB-231-D3H2Ln, IVIS, Bioluminescence, Activins/*metabolism; Animals; Bone Neoplasms/*complications/pathology/physiopathology/secondary; Bone Resorption/*etiology/pathology/physiopathology/*prevention & control; Calcification, Physiologic/drug effects; Cell Line, Tumor; HEK293 Cells; Humans; Mice; Multiple Myeloma/complications/pathology/physiopathology; Neoplasm Transplantation; Organ Size/drug effects; Osteoblasts/drug effects/pathology; *Osteogenesis/drug effects; Osteolysis/blood/complications/physiopathology/prevention & control; Paraproteins/metabolism; Recombinant Fusion Proteins/pharmacology; *Signal Transduction/drug effects; Survival Analysis; Tumor Burden/drug effects
      12. Abstract :
        Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis (p < .01), promotes bone formation (p < .01) and increases bone mass in vivo (p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption (p < .05) and suppression of bone formation (p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis (p < .01), prevents myeloma-induced suppression of bone formation (p < .05), blocks the development of osteolytic bone lesions (p < .05), and increases survival (p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction (p < .001) and inhibits bone metastases (p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/20533325
      14. Call Number :
        PKI @ kd.modi @ 4
      15. Serial :
        10413
      1. Author :
        Tafreshi, N. K.; Huang, X.; Moberg, V. E.; Barkey, N. M.; Sondak, V. K.; Tian, H.; Morse, D. L.; Vagner, J.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2012
      5. Publication :
        Bioconjug Chem
      6. Products :
      7. Volume :
        23
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IVIS, B16-F10-luc-G5, B16F10-luc-G5, B16-F10-luc, B16F10-luc
      12. Abstract :
        The incidence of malignant melanoma is rising more rapidly than that of any other cancer in the United States. The melanocortin 1 receptor (MC1R) is overexpressed in most human melanoma metastases, thus making it a promising target for imaging and therapy of melanomas. We have previously reported the development of a peptidomimetic ligand with high specificity and affinity for MC1R. Here, we have conjugated near-infrared fluorescent dyes to the C-terminus of this ligand via lysine-mercaptopropionic acid linkers to generate MC1R specific optical probes (MC1RL-800, 0.4 nM K(i); and MC1RL-Cy5, 0.3 nM K(i)). Internalization of the imaging probe was studied in vitro by fluorescence microscopy using engineered A375/MC1R cells and B16F10 cells with endogenous MC1R expression. The in vivo tumor targeting of MC1RL-800 was evaluated by intravenous injection of probe into nude mice bearing bilateral subcutaneous A375 xenograft tumors with low MC1R expression and engineered A375/MC1R tumors with high receptor expression. Melanotic B16F10 xenografts were also studied. Fluorescence imaging showed that the agent has higher uptake values in tumors with high expression compared to low (p < 0.05), demonstrating the effect of expression levels on image contrast-to-noise. In addition, tumor uptake was significantly blocked by coinjection of excess NDP-alpha-MSH peptide (p < 0.05). In conclusion, the MC1R-specific imaging probe developed in this study displays excellent potential for the intraoperative detection of regional node involvement and for margin detection during melanoma metastasis resection.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/23116461
      14. Call Number :
        PKI @ kd.modi @ 18
      15. Serial :
        10535
      1. Author :
        Kenneth M Kozloff, Ralph Weissleder and Umar Mahmood
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2007
      5. Publication :
        Journal of Bone and Mineral Research
      6. Products :
      7. Volume :
        22
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        Physiology
      11. Keywords :
        FMT; OsteoSense; ProSense bone mineralization; bone turnover markers; molecular imaging; bisphosphonates; in vivo imaging
      12. Abstract :
        Abstract: FRFP binds to mineral at osteoblastic, osteoclastic, and quiescent surfaces, with accumulation likely modulated by vascular delivery. In vivo visualization and quantification of binding can be accomplished noninvasively in animal models through optical tomographic imaging.

        Introduction: The development of near-infrared optical markers as reporters of bone metabolism will be useful for early diagnosis of disease. Bisphosphonates bind differentially to osteoblastic and osteoclastic surfaces depending on choice of side-chain and dose, and fluorescently tagged bisphosphonates provide a convenient way to visualize these sites. This study examines the ability of a fluorescently labeled pamidronate imaging probe to bind to regions of bone formation and resorption in vivo.

        Materials and Methods: In vitro binding of a far-red fluorescent pamidronate (FRFP) to mineral was assessed using intact and demineralized dentine slices. In vivo, FRFP binding was studied in three models: developing neonatal mouse, bone healing after injury, and metastasis-induced osteolysis and fracture. 3D fluorescence molecular tomographic (FMT) imaging was used to visualize signal deep within the body.

        Results: FRFP binding to bone depends on the quantity of mineral present and can be liberated from the bone during decalcification. In vivo, FRFP binds to surfaces of actively forming bone, as assessed by alkaline phosphatase staining, surfaces undergoing active resorption, as noted by scalloped bone border and presence of osteoclasts, and to quiescent surfaces not involved in formation or resorption. Binding is likely modulated by vascular delivery of the imaging agent to the exposed mineral surface and total quantity of surface exposed.FMT imaging is capable of visualizing regions of bone formation because of a large volume of labeled surface, but like radiolabeled bone scans, cannot discriminate pure osteolysis caused by metastasis.

        Conclusions: FRFP may function as a local biomarker of bisphosphonate deposition to assess interplay between drug and cellular environment or may be combined with other imaging agents or fluorescent cells for the noninvasive assessment of local bone metabolism in vivo.
      13. URL :
        http://onlinelibrary.wiley.com/doi/10.1359/jbmr.070504/references?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.jtitle=Nat%20Med&rft.atitle=Shedding%20light%20onto%20live%20molecular%20targets&rft.volume=9&rf
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4530
      1. Author :
        Asai, T.; Matsushita, S.; Kenjo, E.; Tsuzuku, T.; Yonenaga, N.; Koide, H.; Hatanaka, K.; Dewa, T.; Nango, M.; Maeda, N.; Kikuchi, H.; Oku, N.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        Bioconjug Chem
      6. Products :
      7. Volume :
        22
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        Animals, B16-F10-luc2, B16F10-luc2; Base Sequence; Cell Line, Tumor; Cholesterol/metabolism; Ethylenediamines/*chemistry; Fibrosarcoma/metabolism/pathology; Gene Silencing; Humans; Injections, Intravenous; Liposomes/administration & dosage/chemical; synthesis/*chemistry/pharmacokinetics; Male; Mice; Mice, Inbred BALB C; Molecular Imaging; Phosphoric Acid Esters/*chemistry; Polyethylene Glycols/chemistry; RNA, Small Interfering/genetics/*metabolism; Spectrophotometry, Infrared
      12. Abstract :
        Dicetyl phosphate-tetraethylenepentamine (DCP-TEPA) conjugate was newly synthesized and formed into liposomes for efficient siRNA delivery. Formulation of DCP-TEPA-based polycation liposomes (TEPA-PCL) complexed with siRNA was examined by performing knockdown experiments using stable EGFP-transfected HT1080 human fibrosarcoma cells and siRNA for GFP. An adequate amount of DCP-TEPA in TEPA-PCL and N/P ratio of TEPA-PCL/siRNA complexes were determined based on the knockdown efficiency. Then, the biodistribution of TEPA-PCL modified with poly(ethylene glycol) (PEG) was examined in BALB/c mice. As a result, TEPA-PCL modified with PEG6000 avoided reticuloendothelial system uptake and showed long circulation in the bloodstream. On the other hand, PEGylation of TEPA-PCL/siRNA complexes caused dissociation of a portion of the siRNA from the liposomes. However, we found that the use of cholesterol-conjugated siRNA improved the interaction between TEPA-PCL and siRNA, which allowed PEGylation of TEPA-PCL/siRNA complexes without siRNA dissociation. In addition, TEPA-PCL complexed with cholesterol-conjugated siRNA showed potent knockdown efficiency in stable luciferase-transfected B16-F10 murine melanoma cells. Finally, the biodistribution of cholesterol-conjugated siRNA formulated in PEGylated TEPA-PCL was examined by performing near-infrared fluorescence imaging in Colon26 NL-17 murine carcinoma-bearing mice. Our results showed that tumor targeting with siRNA via systemic administration was achieved by using PEGylated TEPA-PCL combined with active targeting with Ala-Pro-Arg-Pro-Gly, a peptide used for targeting angiogenic endothelium.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/21361311
      14. Call Number :
        PKI @ kd.modi @ 7
      15. Serial :
        10347
      1. Author :
        Valdivia, Y. Alvarado M.; Wong, K.; Cheng He, T.; Xue, Z.; Wong, S. T.
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2011
      5. Publication :
        J Vasc Interv Radiol
      6. Products :
      7. Volume :
        22
      8. Issue :
        N/A
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        IntegriSense, Animals; Cell Line, Tumor; Fiber Optic Technology/*methods; Fluorescent Dyes/*administration & dosage/*diagnostic use; Humans; Injections, Intralesional; Lung Neoplasms/*pathology; Microscopy, Fluorescence/*methods; Molecular Imaging/*methods; Rabbits; Surgery, Computer-Assisted/*methods; Tomography, X-Ray Computed/methods
      12. Abstract :
        PURPOSE: To show the feasibility of computed tomography (CT) image-guided fiberoptic confocal fluorescence molecular imaging in a rabbit lung tumor model. MATERIALS AND METHODS: Eight lung tumor models were created by injection of a VX2 cell suspension. The fluorescent imaging agent IntegriSense 680 was given to the animals 3.5-4 hours before the procedure. CT images were obtained and transferred to the minimally invasive multimodality image-guided (MIMIG) system as a guidance map. A real-time electromagnetically tracked needle was inserted under the visual guidance of the MIMIG system. A second CT image was obtained to confirm the location of the needle tip. Next, fiberoptic fluorescence imaging was acquired along the needle track. Finally, tumor samples were obtained for histopathologic confirmation. RESULTS: All cases were performed during breath-hold. Tumor size was 12.5 mm +/- 1.6; the distance from the chest wall was 2.1 mm +/- 0.5. The needle tip reached the tumor in all cases with an accuracy of 3.3 mm +/- 1.6. Only one skin entry point was necessary, and no needle adjustments were required. No pneumothorax was observed. At least two-fold alpha(v)beta(3) integrin image contrast was detected in the tumor compared with normal lung tissue. Tumor samples were confirmed to have viable VX2 cells and contrast uptake. CONCLUSIONS: The MIMIG system enables effective in situ fluorescence molecular imaging in a needle biopsy lung procedure. In situ alpha(v)beta(3) integrin molecular imaging allows molecular characterization of lung tumors at multiple regions and can be used to guide biopsy procedures.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/22019854
      14. Call Number :
        PKI @ kd.modi @ 14
      15. Serial :
        10383
      1. Author :
        Thomas Reiner, Rainer H. Kohler, Chong Wee Liew, Jonathan Hill, Jason Gaglia, Rohit Kulkarni and Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2010
      5. Publication :
        Bioconjugate Chemistry
      6. Products :
      7. Volume :
        21
      8. Issue :
        7
      9. Page Numbers :
        N/A
      10. Research Area :
        Metabolic Disorders
      11. Keywords :
        Beta-cells; GLP1-R; imaging; targeting; in vivo imaging; VivoTag; AngioSense; Diabetes
      12. Abstract :
        The ability to image and ultimately quantitate beta-cell mass in vivo will likely have far reaching implications in the study of diabetes biology, in the monitoring of disease progression or response to treatment, as well as for drug development. Here, using animal models, we report on the synthesis, characterization of, and intravital microscopic imaging properties of a near infrared fluorescent exendin-4 analogue with specificity for the GLP-1 receptor on beta cells (E4K12-Fl). The agent demonstrated sub-nanomolar EC50 binding concentrations, with high specificity and binding could be inhibited by GLP-1R agonists. Following intravenous administration to mice, pancreatic islets were readily distinguishable from exocrine pancreas, achieving target-to-background ratios within the pancreas of 6:1, as measured by intravital microscopy. Serial imaging revealed rapid accumulation kinetics (with initial signal within the islets detectable within 3 minutes and peak fluorescence within 20 minutes of injection) making this an ideal agent for in vivo imaging.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912453/?tool=pubmed
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4561
      1. Author :
        Neal K. Devaraj; Edmund J. Keliher; Greg M. Thurber; Matthias Nahrendorf; Ralph Weissleder
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Bioconjugate Chemistry
      6. Products :
      7. Volume :
        20
      8. Issue :
        2
      9. Page Numbers :
        N/A
      10. Research Area :
        Cancer
      11. Keywords :
        in vivo imaging; fluorescence molecular tomography
      12. Abstract :
        We report the synthesis and in vivo characterization of an 18F modified trimodal nanoparticle (18F-CLIO). This particle consists of cross-linked dextran held together in core-shell formation by a superparamagnetic iron oxide core and functionalized with the radionuclide 18F in high yield via “click” chemistry. The particle can be detected with positron emission tomography, fluorescence molecular tomography, and magnetic resonance imaging. The presence of 18F dramatically lowers the detection threshold of the nanoparticles, while the facile conjugation chemistry provides a simple platform for rapid and efficient nanoparticle labeling.
      13. URL :
        http://pubs.acs.org/doi/abs/10.1021/bc8004649
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4498
      1. Author :
        Jason R. McCarthy, Purvish Patel, Ion Botnaru, Pouneh Haghayeghi, Ralph Weissleder and Farouc A. Jaffer
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2009
      5. Publication :
        Bioconjugate Chemistry
      6. Products :
      7. Volume :
        20
      8. Issue :
        6
      9. Page Numbers :
        N/A
      10. Research Area :
        Cardiovascular Research
      11. Keywords :
        In vivo imaging; thrombi; VivoTag
      12. Abstract :
        Thrombosis underlies numerous life-threatening cardiovascular syndromes. Development of thrombosis-specific molecular imaging agents to detect and monitor thrombogenesis and fibrinolysis in vivo could improve the diagnosis, risk stratification, and treatment of thrombosis syndromes. To this end, we have synthesized efficient multimodal nanoagents targeted to two different constituents of thrombi, namely, fibrin and activated factor XIII. These agents are targeted via the conjugation of peptide-targeting ligands to the surface of fluorescently labeled magnetic nanoparticles. As demonstrated by in vitro and in vivo studies, both nanoagents possess high affinities for thrombi, and enable mutimodal fluorescence and magnetic resonance imaging.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/19456115
      14. Call Number :
        PKI @ sarah.piper @
      15. Serial :
        4647
      1. Author :
        Jenkins, Darlene E; Oei, Yoko; Hornig, Yvette S; Yu, Shang-Fan; Dusich, Joan; Purchio, Tony; Contag, Pamela R
      2. Title :
      3. Type :
        Journal Article
      4. Year :
        2003
      5. Publication :
        Clinical & experimental metastasis
      6. Products :
      7. Volume :
        20
      8. Issue :
        8
      9. Page Numbers :
        N/A
      10. Research Area :
        N/A
      11. Keywords :
        A549-luc-C8; Animals; Bioware; Cell Line, Tumor; Colonic Neoplasms; Fluorouracil; HT-29-luc-D6 cells; Humans; Image Interpretation, Computer-Assisted; Longitudinal Studies; Luciferases; Luminescent Measurements; Lung Neoplasms; Lymphatic Metastasis; Male; Mice; Mice, SCID; Mitomycin; Models, Biological; Neoplasm Transplantation; PC-3M-luc; Prostatic Neoplasms
      12. Abstract :
        Bioluminescent imaging (BLI) permits sensitive in vivo detection and quantification of cells specifically engineered to emit visible light. Three stable human tumor cell lines engineered to express luciferase were assessed for their tumorigenicity in subcutaneous, intravenous and spontaneous metastasis models. Bioluminescent PC-3M-luc-C6 human prostate cancer cells were implanted subcutaneously into SCID-beige mice and were monitored for tumor growth and response to 5-FU and mitomycin C treatments. Progressive tumor development and inhibition/regression following drug treatment were observed and quantified in vivo using BLI. Imaging data correlated to standard external caliper measurements of tumor volume, but bioluminescent data permitted earlier detection of tumor growth. In a lung colonization model, bioluminescent A549-luc-C8 human lung cancer cells were injected intravenously and lung metastases were monitored in vivo by whole animal imaging. Anesthetized mice were imaged weekly allowing a temporal assessment of in vivo lung tumor growth. This longitudinal study design permitted an accurate, real-time evaluation of tumor burden in the same animals over time. End-point bioluminescence measured in vivo correlated to total lung weight at necropsy. For a spontaneous metastatic tumor model, bioluminescent HT-29-luc-D6 human colon cancer cells implanted subcutaneously produced metastases to lung and lymph nodes in SCID-beige mice. Both primary tumors and micrometastases were detected by BLI in vivo. Ex vivo imaging of excised lung lobes and lymph nodes confirmed the in vivo signals and indicated a slightly higher frequency of metastasis in some mice. Levels of bioluminescence from in vivo and ex vivo images corresponded to the frequency and size of metastatic lesions in lungs and lymph nodes as subsequently confirmed by histology. In summary, BLI provided rapid, non-invasive monitoring of tumor growth and regression in animals. Its application to traditional oncology animal models offers quantitative and sensitive analysis of tumor growth and metastasis. The ability to temporally assess tumor development and responses to drug therapies in vivo also improves upon current standard animal models that are based on single end point data.
      13. URL :
        http://www.ncbi.nlm.nih.gov/pubmed/14713107
      14. Call Number :
        PKI @ catherine.lautenschlager @
      15. Serial :
        8980
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