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Development of AGT-7: An Innovative 99mTc-Labeled Theranostic Platform for Glioblastoma Imaging and Therapy
Stavroula G Kyrkou1, Vasileios-Panagiotis Bistas1, Evangelia-Alexandra Salvanou2
1Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece.
Abstract:
Background: Glioblastoma, the most common malignant primary brain tumor in adults, continues to present a major therapeutic challenge, with a median survival of only 12-15 months and a 5-year survival rate below 2%. Despite aggressive treatment-including maximal surgical excision, radiation, and temozolomide (TMZ) chemotherapy-recurrent disease is nearly universal due to the tumor's infiltrative nature. Objectives: To address the critical need for improved diagnostic and therapeutic strategies for glioblastoma multiforme (GBM), we have developed an innovative theranostic molecule, [99mTc]Tc-AGT-7. Methods: AGT-7 integrates diagnostic and therapeutic modalities comprising [99mTc]Tc-TF (a nuclear medicine imaging agent) and TMZ. The diagnostic component has been tailored to selectively accumulate in glioma mitochondria. A chelating moiety enables radiolabeling with technetium-99m (99mTc) for precise Single-Photon Emission Computed Tomography (SPECT) imaging. The therapeutic arm includes the tethering of a TMZ moiety for localized cytotoxicity. Conclusions: In vitro studies illustrated that AGT-7 has potent cytotoxic effects in GBM cell lines (T98 and U87), with greater efficacy than TMZ, and toxicity assays in zebrafish embryos indicated a favorable safety profile. Biodistribution studies in CFW mice demonstrated that [99mTc]Tc-AGT-7 exhibited a ~10-fold lower heart uptake compared to [99mTc]Tc-TF, implying reduced off-target cardiac localization. This significantly lowers the risk of cardiotoxicity and enhances AGT-7's potential as a glioma-targeted theranostic agent.
Insights
A new theranostic molecule, [99mTc]Tc-AGT-7, shows promise for glioblastoma treatment. It combines imaging and targeted chemotherapy, demonstrating potent anti-cancer effects and reduced cardiac toxicity in preclinical studies.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor with poor prognosis despite standard treatments.
- Tumor recurrence is common due to GBM's infiltrative nature, necessitating improved diagnostic and therapeutic strategies.
- Current therapies for GBM, including surgery, radiation, and temozolomide (TMZ), have limited efficacy.
Purpose of the Study:
- To develop an innovative theranostic molecule, [99mTc]Tc-AGT-7, for improved glioblastoma diagnosis and therapy.
- To integrate diagnostic imaging and targeted chemotherapy into a single agent.
- To evaluate the efficacy and safety of [99mTc]Tc-AGT-7 in preclinical models.
Main Methods:
- Development of AGT-7, a theranostic molecule combining a SPECT imaging agent ([99mTc]Tc-TF) and temozolomide (TMZ).
- Targeting of glioma mitochondria by the diagnostic component.
- Radiolabeling with technetium-99m (99mTc) for SPECT imaging and tethering of TMZ for localized cytotoxicity.
- In vitro studies on GBM cell lines (T98, U87), zebrafish embryo toxicity assays, and biodistribution studies in mice.
Main Results:
- AGT-7 demonstrated potent in vitro cytotoxicity against GBM cell lines, exceeding TMZ's efficacy.
- Toxicity assays in zebrafish embryos indicated a favorable safety profile for AGT-7.
- [99mTc]Tc-AGT-7 showed approximately 10-fold lower heart uptake in mice compared to [99mTc]Tc-TF, suggesting reduced cardiotoxicity.
Conclusions:
- [99mTc]Tc-AGT-7 is a promising theranostic agent for glioblastoma.
- The molecule offers enhanced efficacy and a potentially improved safety profile compared to existing treatments.
- AGT-7's targeted approach reduces off-target effects, particularly cardiac localization, enhancing its therapeutic potential.
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