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

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. 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 [Ga]Ga, [Lu]Lu, and [Ac]Ac was optimized. The binding affinity (K) 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 [Lu]Lu-DOTAGA-IAC distribution data. A pilot study of [Ga]Ga-DOTAGA-IAC and [F]FDG Positron Emission Tomography (PET/CT) imaging was performed in five patients with histopathologically confirmed breast cancer. PET/CT findings were compared between [Ga]Ga-DOTAGA-IAC and [F]FDG in these patients. Radiopharmaceuticals were prepared with high radiochemical purity (>99.9%). K and B 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 [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, [Ga]Ga-DOTAGA-IAC detected the primary lesions in all five patients with a mean standard uptake value (SUV) of 3.94 ± 0.58 compared with [F]FDG (SUV 13.8 ± 6.53). 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 [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.