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A Targeted Radiotheranostic Agent for Glioblastoma: [64Cu]Cu-NOTA-TP-c(RGDfK)
Alireza Mirzaei1, Samia Ait-Mohand1, Prenitha Mercy Ignatius Arokia Doss1
1Department of Medical Imaging and Radiation Sciences, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
Abstract:
Glioblastoma multiforme (GBM) remains one of the most aggressive and treatment-resistant brain tumors, with poor prognosis and limited therapeutic options. Background/Objectives: Integrin αvβ3, a cell surface receptor overexpressed in GBM, specifically binds to cyclic arginine-glycine-aspartate-D-phenylalanine-lysine (c(RGDfK)) motif, making it a valuable target for tumor-specific delivery and PET imaging. This study explores a novel radiotheranostic agent, [64Cu]Cu-NOTA-TP-c(RGDfK), which combines the imaging and therapeutic capabilities of copper-64 (64Cu) and the cytotoxic activity of a terpyridine-platinum (TP) complex, conjugated to c(RGDfK). Methods: A robust protocol was developed for the small-scale preparation of NOTA-TP-c(RGDfK). Comparative cellular studies were conducted using U87 MG glioblastoma (GBM) cells and SVG p12 human astrocytes to evaluate the performance of [64Cu]Cu-NOTA-TP-c(RGDfK) relative to [64Cu]Cu-NOTA-c(RGDfK), [64Cu]Cu-NOTA-TP, natCu-NOTA-TP-c(RGDfK), cisplatin, and temozolomide. Results: 64Cu-radiolabeling of NOTA-TP-c(RGDfK) was achieved with >99% radiochemical purity, and competition assays confirmed high binding affinity to integrin αvβ3 (IC50 = 16 ± 8 nM). Cellular uptake, internalization, and retention studies demonstrated significantly higher accumulation of [64Cu]Cu-NOTA-TP-c(RGDfK) in U87 MG cells compared to control compounds, with 38.8 ± 1.8% uptake and 28.0 ± 1.0% internalization at 24 h. Nuclear localization (6.0 ± 0.5%) and stable intracellular retention further support its therapeutic potential for inducing localized DNA damage. Importantly, [64Cu]Cu-NOTA-TP-c(RGDfK) exhibited the highest cytotoxicity in U87 MG cells (IC50 = 10 ± 2 nM at 48 h), while maintaining minimal toxicity in normal SVG p12 astrocytes. Conclusions: These results highlight [64Cu]Cu-NOTA-TP-c(RGDfK) as a promising targeted radiotheranostic agent for GBM, warranting further preclinical development.
Insights
A novel radiotheranostic agent, [64Cu]Cu-NOTA-TP-c(RGDfK), shows promise for glioblastoma (GBM) treatment. This agent effectively targets GBM cells, exhibiting high cytotoxicity while sparing normal cells, indicating potential for improved GBM therapy.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
- Integrin αvβ3, overexpressed in GBM, is a key target for diagnostic and therapeutic strategies.
- Radiotheranostic agents offer combined imaging and therapeutic benefits for targeted cancer treatment.
Purpose of the Study:
- To develop and evaluate a novel radiotheranostic agent, [64Cu]Cu-NOTA-TP-c(RGDfK), for targeting glioblastoma (GBM).
- To assess the binding affinity, cellular uptake, and cytotoxicity of the novel agent in GBM cells.
Main Methods:
- Synthesis and radiolabeling of [64Cu]Cu-NOTA-TP-c(RGDfK) using copper-64 (64Cu).
- Comparative cellular studies using U87 MG glioblastoma cells and SVG p12 astrocytes.
- Evaluation of binding affinity, cellular uptake, internalization, retention, and cytotoxicity compared to control agents.
Main Results:
- High radiochemical purity (>99%) and strong binding affinity (IC50 = 16 ± 8 nM) to integrin αvβ3 were achieved.
- Significantly higher cellular uptake (38.8 ± 1.8%) and internalization (28.0 ± 1.0%) in U87 MG cells compared to controls.
- Demonstrated potent cytotoxicity (IC50 = 10 ± 2 nM) in U87 MG cells with minimal toxicity in normal astrocytes.
Conclusions:
- [64Cu]Cu-NOTA-TP-c(RGDfK) is a promising targeted radiotheranostic agent for glioblastoma.
- The agent exhibits specific targeting, effective cellular uptake, and potent cytotoxicity against GBM cells.
- Further preclinical development is warranted for this novel GBM therapeutic and diagnostic agent.
