理由：胶质母细胞瘤 (GBM) 由于其异质性和侵袭性，对肿瘤的完全切除提出了重大挑战，强调需要有效的治疗选择。在过去的二十年中，荧光引导手术 (FGS) 使用 5-氨基乙酰丙酸 (5-ALA) 等荧光团来增强肿瘤描绘，受到神经外科医生的青睐。然而，一些低级别肿瘤没有显示示踪剂的任何积累，并且缺乏患者分层是一个重要的限制。自 2000 年以来，人们对内皮素轴在癌症进展中的作用进行了广泛研究。更具体地说，我们的团队已确定在胶质母细胞瘤干细胞中过度表达的内皮素 A 受体 (ETA) 作为 GBM 成像的目标靶标。本研究旨在评估新型临床前双峰成像剂 [89Zr]Zr-axiRA63-MOMIP 作为治疗诊断方法的功效：i) 检测人类 GBM 原位模型中的 ETA 细胞，ii) 实现肿瘤完全切除。方法：单分子多模态成像平台 (MOMIP) - 包含荧光团 (IRDye800CW) 和正电子发射放射性金属螯合剂（去铁胺 B、DFO） - 与靶向 ETA 受体的 axiRA63 抗体缀合，在 GBM 干细胞表面过度表达细胞。注射[89Zr]Zr-axiRA63-MOMIP后48小时，通过正电子发射断层扫描（PET）和光学成像对携带原位人GBM的小鼠进行成像。随后，实施了尸检概念验证 FGS 以及离体分析 (H

Rationale: Glioblastoma (GBM) poses significant challenges regarding complete tumor removal due to its heterogeneity and invasiveness, emphasizing the need for effective therapeutic options. In the last two decades, fluorescence-guided surgery (FGS), employing fluorophores such as 5-aminolevulinic acid (5-ALA) to enhance tumor delineation, has gained attraction among neurosurgeons. However, some low-grade tumors do not show any accumulation of the tracers, and the lack of patient stratification represents an important limitation. Since 2000, endothelin axis has been extensively investigated for its role in cancer progression. More specifically, our team has identified endothelin A receptors (ETA), overexpressed in glioblastoma cancer stem cells, as a target of interest for GBM imaging. This study aims to evaluate the efficacy of a novel preclinical bimodal imaging agent, [89Zr]Zr-axiRA63-MOMIP, as a theranostic approach to: i) detect ETA + cells in an orthotopic model of human GBM, ii) achieve complete tumoral resection. Methods: Monomolecular multimodal imaging platform (MOMIP) - containing both a fluorophore (IRDye800CW) and a chelator for a positron-emitting radiometal (desferroxamine B, DFO) - was conjugated to the axiRA63 antibody targeting ETA receptors, overexpressed on the surface of GBM stem cells. Mice bearing orthotopic human GBM were imaged 48 h post injection of [89Zr]Zr-axiRA63-MOMIP via positron emission tomography (PET) and optical imaging. Subsequently, post-mortem proof-of-concept FGS was implemented as well as ex vivo analyses (H&E staining, autoradiography, serial block face imaging) on brains with resected or unresected tumor to assess the correlation between PET and fluorescence signals. Results: PET imaging of [89Zr]Zr-axiRA63-MOMIP enabled a clear detection of ETA + cells in an orthotopic model of human GBM. Intraoperative optical imaging allowed a near-complete tumor resection together with the visualization of a weak fluorescence signal, after a prolonged exposure time, that was attributed to residual tumor cells via H&E staining. Besides, a qualitative correlation between the signals of both modalities was observed. Conclusions: The use of [89Zr]Zr-axiRA63-MOMIP provides an effective theranostic approach to detect and treat GBM by surgery in a preclinical mouse model. Thanks to the high correlation between PET and fluorescence signal allowing patients stratification, this bimodal agent should have a great potential for clinical translation and should present a significant advantage over non-targeted fluorophores already used in the clinic.© The author(s).