Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1α/OATPs signaling axis
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Changhong Shi1,2, Jason Boyang Wu2, Gina C-Y. Chu2, Qinlong Li2, Ruoxiang Wang2, Caiqin Zhang1, Yi Zhang3, Hyung L. Kim4, Jing Wang5, Haiyen E. Zhau2, Dongfeng Pan3, Leland W.K. Chung2
1Laboratory Animal Center, the Fourth Military Medical University, Xi’an, Shaanxi 710032, China
2Uro-Oncology Research Program, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
3Department of Radiology, the University of Virginia, Charlottesville, VA 22908, USA
4Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
5Department of Nuclear Medicine, Xijing Hospital, the Fourth Military Medical University, Xi’an, Shaanxi 710032, China
Leland W.K. Chung, e-mail: Leland.Chung@cshs.org
Changhong Shi, e-mail: firstname.lastname@example.org
Dongfeng Pan, e-mail: DP3R@hscmail.mcc.virginia.edu
Keywords: HIF-1α, imaging canine cancer, imaging human prostate cancer, near-infrared dye, organic anion-transporting polypeptides
Received: July 13, 2014 Accepted: September 06, 2014 Published: October 25, 2014
Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1α (HIF-1α) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1α stabilizers activated HIF-1α downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1α by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1α/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.
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