Environment-sensitive fluorescent probes targeting mutant IDH1 for in vivo glioma imaging.

BACKGROUND: Surgery serves as a cornerstone in glioma treatment, yet achieving complete resection remains a significant challenge due to the infiltrative nature of these tumors. Microscopic residual lesions frequently lead to recurrence, whereas excessive resection risks damaging critical neurological functions. Fluorescent imaging technology enables the real-time visualization and precise delineation of glioma margins. However, commonly clinical fluorescent agents for gliomas, such as 5-ALA, fluorescein sodium, and ICG, are limited in their widespread application due to low selectivity and sensitivity. Consequently, there is a pressing need to develop novel targeted fluorescent probes capable of achieving highly specific and accurate localization of glioma tissue.

RESULTS: In this study, we developed a new class of small-molecule fluorescent probes targeting the glioma-associated biomarker mutant isocitrate dehydrogenase 1 (mIDH1). Through multi-level evaluation spanning protein, cellular, and in vivo models, MIP01 was identified as the optimal probe. The probe possessed high affinity (Kd = 156 ± 49.9 nM) and selectivity for mIDH1, displaying a significantly enhanced fluorescence response upon binding that enables precise labeling of glioma cells. More importantly, MIP01 demonstrated outstanding performance in orthotopic glioma xenograft models. It efficiently crossed the blood-brain barrier, selectively accumulated in tumor regions, and produced intense fluorescence signals.

SIGNIFICANCE: In conclusion, fluorescent probe MIP01 achieves precise glioma identification through selective mIDH1 labeling in vitro and in vivo, demonstrating considerable potential as a targeted fluorescence imaging agent for delineating tumor margins in mIDH1-positive gliomas.