Novel IDH1-Targeting Fluorescent Probe Enables Intraoperative Visualization and Resection of Glioblastoma

Glioblastoma is the most common and aggressive primary brain tumor. Surgical resection is the mainstay of treatment, and the extent of tumor resection significantly impacts the patient's survival period. Fluorescence imaging can intuitively outline the tumor boundaries with high resolution, offering broad application prospects in tumor surgery navigation. Although 5-ALA and fluorescent probes targeting CD36, EGFR, etc. have been reported for intraoperative fluorescence-guided glioma surgery, the substantial interpatient heterogeneity of glioblastoma limits their ability to effectively image tumors in a subset of patients. In this study, we developed a novel fluorescent probe, QM-SO₃H, that targets the wild-type IDH1 enzyme to enable intraoperative navigation for glioblastoma (GBM). This probe was designed using a sulfonated quinoline-malononitrile framework with aggregation-induced emission (AIE) characteristics, achieving fluorescence "turn-on" through a restricted intramolecular rotation mechanism upon binding to the IDH1 enzyme. It exhibited an excellent, highly selective fluorescence response to the IDH1 enzyme and can specifically label and track the dynamic changes of the IDH1 enzyme at the cellular level. In an orthotopic U87Luc GBM xenograft model, QM-SO₃H could effectively penetrate the impaired blood-brain barrier in tumors (BBTB) and specifically light up tumors with excellent biocompatibility. Notably, the probe can clearly delineate tumor boundaries, guide complete surgical resection, and even detect microtumors with a diameter of less than 1 mm. Our study established a novel glioblastoma imaging strategy by targeting the IDH1 enzyme, offering a promising alternative approach for fluorescence-guided tumor resection in GBM patients exhibiting high IDH1 expression. Additionally, the probe QM-SO₃H can also serve as a valuable visualization tool for investigating IDH1-associated pathophysiology.