Optical imaging of gastric cancer with near-infrared heptamethine carbocyanine fluorescence dyes.

Ningning Zhao,Caiqin Zhang,Bing Bai,Changhong Shi,Hai Zhang,Yong Zhao,Jiaze An,Jason Boyang Wu

doi:10.18632/oncotarget.10031

Ningning Zhao, Caiqin Zhang + Show 6 more

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https://doi.org/10.18632/oncotarget.10031

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Abstract

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the tumor-specific targeting ability of NIRF heptamethine carbocyanine MHI-148 dye in cultured gastric cancer cells, gastric cancer cell-derived and patient-derived tumor xenograft (PDX) models. We show that the NIRF dye specifically accumulated in tumor regions of both xenograft models, suggesting the potential utility of the dye for tumor-specific imaging and targeting in gastric cancer. We also demonstrated significant correlations between NIRF signal intensity and tumor volume in PDX models. Mechanistically, the higher cellular uptake of MHI-148 in gastric cancer cells than in normal cells was stimulated by hypoxia and activation of a group of organic anion-transporting polypeptide (OATP) genes. Importantly, this NIRF dye was not retained in inflammatory stomach tissues induced by gastric ulcer in mice. In addition, fresh clinical gastric tumor specimens, when perfused with NIR dye, exhibited increased uptake of NIR dye in situ. Together, these results show the possibility of using NIRF dyes as novel candidate agents for clinical imaging and detection of gastric cancer.

Highlights

Near-infrared fluorescence (NIRF) dyes are a class of polycyanine heterocyclic compounds that are formed with large π-conjugated systems composed of heterocyclic rings or aromatic rings at both ends or in the middle and intramolecular polymethine chains [1]
The NIRF signal was exclusively observed in GFPpositive SGC-7901 cells but not the other green fluorescence protein (GFP)-negative GES cells (Figure 1B), suggesting the preferential uptake and retention of MHI-148 in gastric cancer cells but not normal cells
Recent evidence has further indicated the association of dysregulated expression of organic anion-transporting polypeptide (OATP) with cancer development, including gastric cancer [19,20,21]. Given these common features shared by gastric cancer and other types of cancers, such as tumor hypoxia and aberrant OATP expression, we extended our previous findings to examine whether gastric cancer cells may use similar mechanisms to take up and retain NIRF dyes

Summary

Introduction

Near-infrared fluorescence (NIRF) dyes are a class of polycyanine heterocyclic compounds that are formed with large π-conjugated systems composed of heterocyclic rings or aromatic rings at both ends or in the middle and intramolecular polymethine chains [1]. We previously identified and synthesized a unique group of NIRF heptamethine carbocyanine dyes as dual imaging and targeting agents, including MHI-148 and IR-783 [7, 8] These dyes could be used for direct recognition of human genitourinary tumor cells, and showed preferential uptake in tumor cells but not normal cells in a variety of preclinical and clinical model systems [9, 10]. The dye uptake is stimulated in part by tumor hypoxia and activated hypoxia-inducible factor 1α (HIF1α)/organic anion-transporting polypeptide (OATP) signaling [7, 13] Whether these dyes possess the potential to bind gastric cancer and associated malignant events remains to be explored

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