Advancing Cancer Theranostics Through Integrin αVβ3-Targeted Peptidomimetic IAC: From Bench to Bedside

Introduction: The expression of alpha-five beta-three (αVβ3) integrins is upregulated in various malignancies undergoing angiogenesis. The development of integrin antagonists as diagnostic probes makes the αVβ3 integrin a suitable candidate for targeting tumor angiogenesis. The goal of this study was to optimize the radiolabeling and evaluate the potential of conjugated integrin antagonist carbamate (IAC), a peptidomimetic, as a theranostic radiopharmaceutical for targeting tumor angiogenesis. Methodology: Radiolabeling of DOTAGA [2,2′,2”–{10-(2,6-dioxotetrahydro-2H-pyran-3-yl)−1,4,7,10-tetraazacyclododecane-1,4,7-triyl} triacetic-acid]-IAC with [ 68 Ga]Ga, [ 177 Lu]Lu, and [ 225 Ac]Ac was optimized. The binding affinity (K d ) of DOTAGA-IAC for the αVβ3 receptor and cancer cell lines was quantified. The biodistribution studies were conducted in healthy Wistar rats. Dosimetry analysis was performed on [ 177 Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [ 68 Ga]Ga-DOTAGA-IAC and [ 18 F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [ 68 Ga]Ga-DOTAGA-IAC and [ 18 F]FDG in these patients. Results: Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). K d and B max measurements were 15.02 nM and 417 fmol for αVβ3 receptor protein: 115.7 nM and 295.3 fmol for C6 glioma cells. Biodistribution studies in rats suggested the excretion via kidneys and partially through the hepatobiliary route. The effective dose of [ 177 Lu]Lu-DOTAGA-IAC was found to be 0.17 mSv/MBq. The dynamic study in patients revealed the optimal imaging time to be 30–35 mins postadministration. Out of the cohort, [ 68 Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUV max ) of 3.94 ± 0.58 compared with [ 18 F]FDG (SUV max 13.8 ± 6.53). Conclusion: The study demonstrates that DOTAGA-IAC exhibits strong binding to αVβ3 integrin, positioning it as a promising PET agent for assessing primary and metastatic cancers. The outcomes from the pilot study suggest the potential of [ 68 Ga]Ga-DOTAGA-IAC PET/CT in breast carcinoma diagnosis. While recognizing the theranostic potential of DOTAGA-IAC for αVβ3 integrin-expressing tumors, further clinical investigations are warranted to comprehensively assess therapeutic efficacy.