Abstract 3913: Hypoxia-mediated cancer imaging by a novel class of near-infrared (NIR) heptamethine cyanine dyes.

Abstract

Abstract Near-infrared (NIR) fluorescence imaging has great potential for noninvasive tumor detection. In this study, we describe a novel hypoxia-mediated mechanism underlying a group of heptamethine cyanine dyes, MHI-148 and IR-783, which we developed previously that show tumor-specific targeting properties in cancer cells and living animals (Yang et al., Clin Cancer Res 2010, 16:2833-44 and J Urol 2013, in press). Hypoxia is a common condition found in a wide range of tumors, and mediates many aspects of cancer progression at both tissue and single-cell levels. Using a hypoxia-sensitive luciferase reporter construct (5HREp-ODD-luc) to assess dynamic and real-time tumor hypoxia, in vivo and ex vivo dual-modality imaging studies of human prostate cancer (PCa) growth in nude mice indicate superimposed distribution of NIR signals with hypoxia in tumors. Hypoxia and hypoxic mimickers augment NIR dye uptake in multiple human and murine cell lines representing different types of cancer. We determined that the increased dye uptake under hypoxic conditions was mediated by hypoxia-inducible factor 1α (HIF1α) both in vitro and in vivo. Using cDNA microarray analysis, we identified a group of organic anion-transporting polypeptide (OATP) genes (e.g. OATP1B3, OATP2B1 and OATP5A1), which were highly inducible by hypoxia/HIF1α in PCa cells. We further showed increased co-expression of HIF1α and a representative OATP1B3 gene upon PCa progression in clinical specimens. Pharmacological inhibition or genetic silencing of the OATP1B3 gene reduced the uptake of NIR dyes in tumor cells and tissues. Moreover, hypoxia/HIF1α up-regulates the transcriptional and translational expression of OATP1B3 in PCa, and HIF1α directly binds to a hypoxia response element in the OATP1B3 promoter determined by chromatin immunoprecipitation assays. In addition, we applied NIR dyes for clinical detection of renal cell carcinomas, which shows consistent results with clinical diagnostic tests, and importantly, the HIF1α/OATP1B3 signaling was manifested in these tumors. Together, we provide for the first time the molecular mechanisms of specific NIR dye uptake in cancer via tumor hypoxia and HIF1α/OATPs signals, and present clinical evidence for its potential future applications in cancer detection, prognosis, and therapy. Citation Format: Jason Boyang Wu, Chen Shao, Xiangyan Li, Peizhen Hu, Yi-Ting Chen, Xiaoliang Dou, Divya Sahu, Wei Li, Hiroshi Harada, Ruoxiang Wang, Haiyen E. Zhau, Leland W.K. Chung. Hypoxia-mediated cancer imaging by a novel class of near-infrared (NIR) heptamethine cyanine dyes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3913. doi:10.1158/1538-7445.AM2013-3913