Antitumor efficacy and safety of locoregional [¹⁷⁷Lu]Lu-RM26 radionuclide therapy in glioblastoma.

Abstract

Glioblastoma multiforme (GBM) remains an aggressive brain malignancy with dismal prognosis despite current standard-of-care therapies. The gastrin-releasing peptide receptor (GRPR) is overexpressed in gliomas and represents a potential therapeutic target. However, systemic radionuclide delivery is limited by poor tumor penetration and off-target toxicity. GRPR expression and prognostic relevance were analyzed using Chinese Glioma Genome Atlas and a clinical-trial dataset, respectively at the transcriptomic and protein levels. [¹⁷⁷Lu]Lu-RM26, a lutetium-177-labeled GRPR-targeting antagonist, was evaluated in vitro, and administered intratumorally via convection-enhanced delivery in an orthotopic GL261^Fluc+ glioblastoma model. Pharmacokinetic characteristics, including tumor retention and biodistribution, were evaluated by serial single-photon emission computed tomography and gamma-counting. Efficacy was assessed by tumor volume, bioluminescence signal, and overall survival. Safety was evaluated through body weight monitoring, neurological scoring, rotarod testing, hematology, and immunohistochemical staining. Mechanistic insights were obtained via bulk RNA-sequencing and Western blotting. Higher GRPR expression correlated with poorer-prognosis glioma subtypes and reduced survival. In vitro assays showed dose-dependent inhibition of GL261^Fluc+ cell viability, proliferation, and invasion. Locoregional [¹⁷⁷Lu]Lu-RM26 administration led to prolonged tumor retention (74.7 h), high absorbed dose (2.71 × 10⁶ mGy·MBq^- 1), and minimal off-target uptake. Treated mice exhibited marked tumor growth inhibition, reduced bioluminescence signal, and extended survival compared to controls. No significant short-term systemic toxicity or neurological impairment was observed. Transcriptome and Western blotting findings were consistent with DNA replication stalling and G2/M arrest. Locoregional [¹⁷⁷Lu]Lu-RM26 therapy enables sustained, tumor-specific β-radiation with minimal systemic exposure, representing a promising locoregional strategy for GRPR-positive GBM.