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A Potential Boron Neutron Capture Therapy Agent Selectively Suppresses High-Grade Glioma: In Vitro and in Vivo
Catalina Alamón1,2, Belén Dávila1, María Fernanda García3
1Grupo de Química Orgánica Medicinal, Instituto de Química Biológica, Facultad de Ciencias, Universidad de la República, Montevideo 11400, Uruguay.
Abstract:
Glioblastoma (GBM), as the most central nervous system (CNS) intractable disease, has spoiled millions of lives due to its high mortality. Even though several efforts have been made, the existing treatments have had limited success. In this sense, we studied a lead compound, the boron-rich selective epidermal growth factor receptor (EGFR)-inhibitor hybrid 1, as a potential drug for GBM treatment. For this end, we analyzed the in vitro activity of hybrid 1 in a glioma/primary astrocytes coculture, studying cellular death types triggered by treatment with this compound and its cellular localizations. Additionally, hybrid 1 concentrated boron in glioma cells selectively and more effectively than the boron neutron capture therapy (BNCT)-clinical agent 10B-l-boronophenylalanine and thus displayed a better in vitro-BNCT effect. This encouraged us to analyze hybrid 1 in vivo. Therefore, immunosuppressed mice bearing U87 MG human GBM were treated with both 1 and 1 encapsulated in a modified liposome (recognized by brain-blood barrier peptide transporters), and we observed a potent in vivo per se antitumor activity (tumor size decrease and animal survival increase). These data demonstrate that 1 could be a promising new targeted therapy for GBM.
Insights
A novel boron-rich compound, hybrid 1, shows promise for treating glioblastoma (GBM). It selectively targets cancer cells and demonstrates potent anti-tumor effects both in vitro and in vivo, offering a potential new therapy for this challenging brain cancer.
Area of Science:
- Neuro-oncology
- Drug Discovery
- Boron Neutron Capture Therapy (BNCT)
Background:
- Glioblastoma (GBM) is a highly fatal and treatment-resistant central nervous system (CNS) cancer.
- Current GBM treatments have limited efficacy, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the potential of a boron-rich, selective epidermal growth factor receptor (EGFR)-inhibitor hybrid 1 as a GBM therapeutic agent.
- To evaluate the in vitro and in vivo efficacy of hybrid 1 for GBM treatment.
Main Methods:
- In vitro analysis of hybrid 1 in glioma/primary astrocytes coculture, assessing cell death and localization.
- Comparative analysis of boron concentration in glioma cells versus the BNCT agent 10B-l-boronophenylalanine.
- In vivo studies using U87 MG human GBM xenografts in mice, treated with hybrid 1 and liposome-encapsulated hybrid 1.
Main Results:
- Hybrid 1 demonstrated selective and effective boron accumulation in glioma cells, outperforming 10B-l-boronophenylalanine.
- Hybrid 1 exhibited a superior in vitro-BNCT effect compared to the clinical agent.
- In vivo administration of hybrid 1 (both free and liposome-encapsulated) resulted in significant tumor size reduction and increased animal survival.
Conclusions:
- Hybrid 1 displays potent per se antitumor activity against GBM.
- The compound's ability to selectively target glioma cells and enhance BNCT effects makes it a promising candidate for novel GBM therapy.
- Liposomal encapsulation may further improve the delivery and efficacy of hybrid 1 for brain-blood barrier penetration.
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