Integrin-based Peptidomimetic IAC as a Theranostic Radiopharmaceutical for Targeting Tumor Angiogenesis

Introduction: Integrin Antagonist Carbamate Derivative (IAC) is a promising peptidomimetic agent with a high affinity for αVβ3 integrin. The overexpression of αVβ3 integrin in various malignancies and non-expression in normal or non-proliferating cells makes it a suitable candidate for therapeutic target. This study aimed to optimize the radiolabeling and assess the potential of the conjugated Integrin Antagonist Carbamate (IAC) as a theranostic radiopharmaceutical for effectively targeting tumor angiogenesis.

Methods: Radiolabeling of DOTAGA-IAC with [⁶⁸Ga]Ga and [¹⁷⁷Lu]Lu was optimized. The binding affinity (Kd) for the αVβ3 receptor, MCF-7, Hep-G2, and C6 glioma cell lines was quantified. The biodistribution studies were performed in healthy Wistar rats. Dosimetry analysis was performed using OLINDA/EXM on [¹⁷⁷Lu]Lu-DOTAGA-IAC animal distribution data to estimate radiation doses for human organs. The pilot study was performed in histopathologically proven breast cancer patients (n=5). The dynamic study was employed to determine the optimal imaging time for [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT. The findings of [⁶⁸Ga]Ga-DOTAGA-IAC were compared to [¹⁸F]F-FDG PET/CT.

Results: Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). Kd and Bmax measurements were 15.02 nM and 417 fmol for αVβ3 receptor: 115.7 nM, and 295.3 fmol for C6 glioma cells. MCF-7 and Hep-G2 cell lines served as negative controls and showed no specific binding for [⁶⁸Ga]Ga-DOTAGA-IAC. Biodistribution studies in Wistar rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [¹⁷⁷Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq and the highest radiation dose was found for osteogenic cells (0.313 mSv/MBq). The dynamic study in patients revealed the optimal imaging time to be 30-35 mins post-administration. Out of the cohort, [⁶⁸Ga]Ga-DOTAGA-IAC detected the primary lesions in all 5 patients with a mean SUV_max of 3.94 ± 0.58 as compared to ¹⁸F-FDG (SUV_max 13.8 ± 6.53). [⁶⁸Ga]Ga-DOTAGA-IAC was also able to delineate the skull lesions that were not apparent on [¹⁸F]F-FDG.

Conclusions: The study demonstrates that IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The dosimetry analysis showed favorable radiation dose estimates of [¹⁷⁷Lu]Lu-DOTAGA-IAC for human organs. Encouraging pilot study outcomes suggest the potential of [⁶⁸Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. These findings underscore DOTAGA-IAC’s theranostic potential for integrin αVβ3 expressing tumors while acknowledging the need for further clinical investigations to assess therapeutic efficacy.