Translational development of an SGLT2-targeted near-infrared contrast agent for intraoperative imaging of early-stage lung cancer.

Abstract

Background: Non-small cell lung cancer (NSCLC) is increasingly diagnosed at early stages, yet intraoperative localization of small and subsolid lesions remains challenging. Intraoperative molecular imaging (IMI) using tumor-targeted tracers is effective in many cancers; however, no available optical agents are specific for precursor or early-stage NSCLC. Sodium-glucose cotransporter 2 (SGLT2) is upregulated in in situ and minimally invasive lung cancers. This study aimed to develop and validate GlucoGlo, a novel SGLT2-targeted near-infrared (NIR) contrast agent, for IMI in early-stage NSCLC.

Results: GlucoGlo, an SGLT2-targeted fluorescent tracer, was developed and assessed for specificity and efficacy in targeting and detecting NSCLC. Its SGLT2-specific binding was assessed by fluorescence imaging in in vitro and in vivo murine NSCLC models. Mice pretreated with an SGLT2 inhibitor were used to confirm on target binding. GlucoGlo's performance in detecting residual tumor after resection was compared to conventional visualization and palpation. GlucoGlo selectively bound SGLT2-expressing NSCLC cell lines in vitro with minimal fluorescent signal seen in negative controls. In vivo, it accumulated in flank xenografts at clinically relevant doses (peak signal to background ratio (SBR) of 6.85 at 48 h) without toxicity. Fluorescent signal was eliminated with pretreatment with a non-fluorescent SGLT2 inhibitor, confirming target specificity. Histopathologic analysis further confirmed the selective tumor accumulation. In a murine partial-resection model, GlucoGlo exhibited significantly greater sensitivity for detecting residual tumor compared to conventional visualization and palpation in resection models (100% vs. 62.5%; p < 0.01). In ex-vivo human lung tissue, GlucoGlo accurately identified pulmonary malignancy and had significantly greater mean fluorescence in tumor areas compared to normal lung (25,218 vs. 3,371 a.u., respectively, SBR: 7.57; p = 0.009).

Conclusion: GlucoGlo demonstrated high sensitivity and specificity for SGLT2 in preclinical models of NSCLC, supporting its potential for clinical translation in intraoperative detection of ground glass opacities and early-stage lung cancer.