Development of AGT-7: An Innovative 99mTc-Labeled Theranostic Platform for Glioblastoma Imaging and Therapy

<b>Background</b>: 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. <b>Objectives:</b> To address the critical need for improved diagnostic and therapeutic strategies for glioblastoma multiforme (GBM), we have developed an innovative theranostic molecule, [^99mTc]Tc-<b>AGT-7</b>. <b>Methods</b>: <b>AGT-7</b> 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. <b>Conclusions</b>: In vitro studies illustrated that <b>AGT-7</b> 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-<b>AGT-7</b> 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 <b>AGT-7</b>'s potential as a glioma-targeted theranostic agent.