Abstract
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.
Highlights
Near-infrared (NIR) heptamethine carbocyanine dyes are a new class of heterocyclic polymethine cyanine compounds with significant advantages for in vivo imaging due to their high extinction coefficients and large Stokes’ shifts, capable of generating strong fluorescence emission at the range of 700–1000 nm [1,2,3]
Tumor histology and the specific NIR dye uptake were further confirmed by hematoxylin and eosin (H&E) staining and fluorescence microscopic analysis of frozen sections, respectively (Figure 1C)
Primary cultures of normal canine prostate and mammary gland epithelial cells were used as normal controls for ACE1 and CHMp-5b cells, respectively (Figure 5C). These results suggest that the specific and higher uptake and accumulation of NIR dye by canine and human cancer tissues could be mediated by hypoxia-induced hypoxiainducible factor-1α (HIF-1α) and specific organic anion-transporting polypeptide (OATP)
Summary
Near-infrared (NIR) heptamethine carbocyanine dyes are a new class of heterocyclic polymethine cyanine compounds with significant advantages for in vivo imaging due to their high extinction coefficients and large Stokes’ shifts, capable of generating strong fluorescence emission at the range of 700–1000 nm [1,2,3]. They can be detected with ease with little interference from auto-fluorescence often generated from tissue background [4]. OATPs may play a key role in determining the specific uptake of NIR dyes by cancer cells [9, 10]
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