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.

Review on near-infrared heptamethine cyanine dyes as theranostic agents for tumor imaging, targeting, and photodynamic therapy

“…85 At the molecular level, organic anion-transporting polypeptides (OATPs), a group of cell membrane-bound solute carriers, have been shown to play a key role facilitating the delivery of NIRF dyes into tumor cells. 5,19,20,22,28,30 This preferential uptake of heptamethine cyanine moiety in tumor is shown to be correlated with enhanced expression of certain type of OATPs in variety of cancer cell types. There are 11 known human OATPs classified into six families and subfamilies on the basis of their amino acid sequence homologies.…”

“…Further quantitative analysis indicated a sixfold increase of MHI-148 dye uptake intensity in tumors relative to normal tissues, with coregistered tumor regions and fluorescence signals confirmed by pathologic analyses. 20 This pioneering study strongly suggests the potential clinical utility of these attractive NIRF agents.…”

“…5,6,15,16,20,22 For example, Pz 247, a chiral porphyazine NIRF agent without chemical conjugation, show tumor-targeting property and exhibited preferential retention in the tumor cells of human breast tumor xenografts subcutaneously implanted in mice. 46 Heptamethine cyanine dyebased NIRF imaging is becoming an attractive modality for cancer detection with the acquisition of real-time pathophysiologic information.…”

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

“…For example, the OATP inhibitor bromosulfophthalein (BSP) suppressed the accumulation in tumor cells of IR-783 (65), MHI-148 (65,67), and IR-780 iodide (99), primarily through inhibition of OATP1B3 (67,99) (Table III). Further studies indicated that OATP1B3 expression and related MHI-148 accumulation were induced by hypoxia (67).…”

“…For example, the OATP inhibitor bromosulfophthalein (BSP) suppressed the accumulation in tumor cells of IR-783 (65), MHI-148 (65,67), and IR-780 iodide (99), primarily through inhibition of OATP1B3 (67,99) (Table III). Further studies indicated that OATP1B3 expression and related MHI-148 accumulation were induced by hypoxia (67). In addition to diagnostic applications, IR-780's accumulation within tumor cells was also associated with inhibition of cell growth in vitro and of tumor recurrence in the mouse syngeneic Lewis lung carcinoma xenograft model, suggesting that IR-780 could be used as a theranostic agent for the suppression of tumor recurrence (100).…”