Ortmeyer Welch Katherine, McGovern Kelly Anne, Chen Lydia, Krouse Ryan, Guo Kevin, Huang Jeffrey, Brown Michael, Mlakar Jake, Bandi Venu, Holt David, Zhang Paul, Singhal Sunil
Division of Thoracic Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Clinical Studies, University of Pennsylvania Veterinary Hospital, Philadelphia, PA, 19104, USA.
Mol Imaging Biol. 2025 Jul 14. doi: 10.1007/s11307-025-02029-w.
Lung cancer is increasingly diagnosed at early stages, but intraoperative localization of early lesions remains challenging. Intraoperative molecular imaging (IMI) aids in localization of tumors during surgery; however, no optical agents are targeted specifically for early-stage lesions. The sodium-glucose cotransporter 2 (SGLT2) has been implicated in early lung carcinogenesis. This study aimed to describe SGLT2 expression in early-stage lung adenocarcinoma (LUAD) and develop and validate a novel SGLT2-targeted near-infrared (NIR) contrast agent, GlucoGlo, for imaging LUAD.
SGLT2 expression was confirmed by immunohistochemistry (IHC) in human samples. GlucoGlo optical properties were characterized and compared to common NIR dyes. Sensitivity and specificity for SGLT2 were assessed using preclinical in vitro and in vivo mouse models.
On IHC, stage I LUAD displayed higher SGLT2 expression than stage II-III LUAD and normal lung tissue. GlucoGlo exhibited similar depth of penetration and resolution to FDA-approved contrast agents. SGLT2-expressing cell lines treated with GlucoGlo displayed higher fluorescence than the control cell line, confirming SGLT2-dependent uptake. Fluorescence increased with both incubation time and GlucoGlo concentration. Glucose and unconjugated GlucoGlo ligand competitively inhibited GlucoGlo in a dose-dependent manner, indicating high affinity and specificity. GlucoGlo selectively accumulated in SGLT2-expressing flank xenografts, with mean SBR of 2.23 and was inhibited by pretreatment with unconjugated GlucoGlo ligand.
These findings support the potential of GlucoGlo as a targeted IMI contrast agent for early-stage LUAD, and they provide a foundation for future in vivo studies and translational development.
肺癌越来越多地在早期被诊断出来，但早期病变的术中定位仍然具有挑战性。术中分子成像（IMI）有助于手术期间肿瘤的定位；然而，目前尚无专门针对早期病变的光学造影剂。钠-葡萄糖协同转运蛋白2（SGLT2）与早期肺癌发生有关。本研究旨在描述SGLT2在早期肺腺癌（LUAD）中的表达，并开发和验证一种新型的靶向SGLT2的近红外（NIR）造影剂GlucoGlo，用于LUAD成像。
通过免疫组织化学（IHC）在人体样本中确认SGLT2的表达。对GlucoGlo的光学特性进行了表征，并与常见的近红外染料进行了比较。使用临床前体外和体内小鼠模型评估了GlucoGlo对SGLT2的敏感性和特异性。
在免疫组织化学检测中，I期LUAD显示出比II-III期LUAD和正常肺组织更高的SGLT2表达。GlucoGlo的穿透深度和分辨率与FDA批准的造影剂相似。用GlucoGlo处理的表达SGLT2的细胞系显示出比对照细胞系更高的荧光，证实了SGLT2依赖性摄取。荧光随孵育时间和GlucoGlo浓度的增加而增加。葡萄糖和未结合的GlucoGlo配体以剂量依赖性方式竞争性抑制GlucoGlo，表明其具有高亲和力和特异性。GlucoGlo选择性地积聚在表达SGLT2的侧腹异种移植瘤中，平均信号背景比为2.23，并且未结合的GlucoGlo配体预处理可抑制这种积聚。
这些发现支持了GlucoGlo作为早期LUAD靶向IMI造影剂的潜力，并为未来的体内研究和转化开发奠定了基础。
