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Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIF1?/OATPs signaling axis.

ABSTRACT: Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly mediated by hypoxia-inducible factor 1? (HIF1?). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1? was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1?/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy.

SUBMITTER: Wu JB

PROVIDER: S-EPMC4180424 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIF1α/OATPs signaling axis.

Wu Jason Boyang JB Shao Chen C Li Xiangyan X Shi Changhong C Li Qinlong Q Hu Peizhen P Chen Yi-Ting YT Dou Xiaoliang X Sahu Divya D Li Wei W Harada Hiroshi H Zhang Yi Y Wang Ruoxiang R Zhau Haiyen E HE Chung Leland W K LW

Biomaterials 20140621 28

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly ...[more]

PMID: 24957295

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Project description:PURPOSE:Near-infrared fluorescence (NIRF) imaging has been widely used in preclinical studies; however, its low tissue penetration represents a daunting problem for translational clinical imaging of neurodegenerative diseases. The retina is known as an extension of the central nerve system (CNS), and it is widely considered as a window to the brain. Therefore, the retina can be considered as an alternative organ for investigating neurodegenerative diseases, and an eye represents an ideal NIRF imaging organ, due to its minimal opacity. PROCEDURES:NIRF ocular imaging (NIRFOI), for the first time, was explored for imaging of Alzheimer's disease (AD) via utilizing "smart" fluorescent probes CRANAD-X (X = - 2, - 3, - 30, - 58, and - 102) for amyloid beta (Aβ), and CRANAD-61 for reactive oxygen species (ROS). Mice were intravenously injected the fluorescence dyes and images from the eyes were captured with an IVIS imaging system at different time points. RESULTS:All of the tested NIRF probes could be used to differentiate transgenic AD mice and WT mice, and NIRFOI could provide much higher sensitivity for imaging Aβs than NIRF brain imaging did. Our data suggested that NIRFOI could capture the imaging signals from both soluble and insoluble Aβ species. Moreover, we demonstrated that NIRFOI with CRANAD-102 could be used to monitor the therapeutic effects of BACE-1 inhibitor LY2811376. Compared to NIRF brain imaging, NIRFOI provided a larger change of Aβ levels before and after LY2811376 treatment. In addition, we demonstrated that CRANAD-61 could be used to image reactive oxygen species in the eyes. CONCLUSION:The large detection margin by NIRFOI is very important for both diagnosis and therapy response monitoring. Compared to fluorescence microscopic imaging, NIRFOI captures signals with a wide angle (large field of view (FOV)) and can be used to detect soluble Aβs. We believe that NIRFOI has remarkable translational potential for future human studies and can be a potential imaging technology for fast, cheap, accessible, and reliable screening of AD in the future.

Dataset Information

Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIF1?/OATPs signaling axis.

Publications

Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIF1α/OATPs signaling axis.

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