title: Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIF1α/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 1α (HIF1α). 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 HIF1α 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 HIF1α/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.
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Jason Boyang
authors: JB
authors: Wu
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors: Chen
authors: C
authors: Shao
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Xiangyan
authors: X
authors: Li
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Laboratory Animal Center, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors: Changhong
authors: C
authors: Shi
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Qinlong
authors: Q
authors: Li
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Peizhen
authors: P
authors: Hu
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Yi-Ting
authors: YT
authors: Chen
authors: Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors: Xiaoliang
authors: X
authors: Dou
authors: Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors: Divya
authors: D
authors: Sahu
authors: Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
authors: Wei
authors: W
authors: Li
authors: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors: Hiroshi
authors: H
authors: Harada
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Yi
authors: Y
authors: Zhang
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Ruoxiang
authors: R
authors: Wang
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Haiyen E
authors: HE
authors: Zhau
authors: Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: Leland.Chung@cshs.org.
authors: Leland W K
authors: LW
authors: Chung
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000737:chemistry; D003287:Contrast Media / Q000737:chemistry; D018450:Disease Progression; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D019265:Spectroscopy, Near-Infrared
chemical_list: D004396:Coloring Agents; D003287:Contrast Media; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Cancer imaging; HIF1α; Hypoxia; Near-infrared dyes; Organic anion-transporting polypeptides