IMG-142. Evaluating specificity and cross-species reactivity of white matter tract fluorophores in glioblastoma

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Abstract Intraoperative preservation of white matter tracts (WMTs) is critical for ensuring optimal functional outcomes in brain tumor surgery. Fluorescence imaging using oxazine-based biomarkers with high affinity to white matter and high blood-brain barrier penetration have been shown to delineate white matter with high signal-to-background ratios in healthy animal models. We present a novel fluorescence-guided surgery (FGS) approach using these WMT-specific fluorophores validated across species and pathological states. Our aim is to characterize the performance of these biomarkers in glioblastoma (GBM) mouse models and to evaluate cross-species reactivity in human tissue, thereby assessing their suitability for intraoperative use in humans. We evaluate three such previously-identified fluorophores in ex-vivo coronal brain slices from tumor-bearing mice, and ex-vivo human GBM tissue. We use an orthotopic GBM mouse model following implantation of gl261-EGFP cells. These mice received 200 mg/kg 5-aminolevulinic acid (ALA) via intraperitoneal injection as well as either intravenous, intraperitoneal or topical administration of the WMT fluorophore. Fresh human brain tissue from a GBM patient undergoing supramaximal resection was topically stained with WMT fluorophores and assessed ex-vivo for fluorophore binding and WMT selectivity. We imaged all ex-vivo samples with a custom fluorescence imaging system, both pre- and post-staining, incorporating protoporphyrin IX (PpIX) as the tumor biomarker, followed by histopathological evaluation. In normal and tumor-bearing mice, the WMT fluorophores demonstrated strong and selective WMT labeling with high signal-to-background ratios (SBRs). Human biopsy tissue revealed strong fluorescence in white matter areas post-staining but no fluorescence pre-staining, supporting specific cross-reactivity in humans as well. WMT-specific fluorophores are therefore promising agents for real-time, intraoperative FGS visualization of WMT. Cross-validation between mice and human tissues show their potential for clinical translation in GBM patients as surgical adjuncts, helping in preserving critical WMTs.

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