1. Advancing Cancer Theranostics Through Integrin αVβ3-Targeted Peptidomimetic IAC: From Bench to Bedside.
- Author
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Pandey S, Kaur G, Rana N, Chopra S, Rather I, Kumar R, Laroiya I, Chadha VD, Satz S, Stabin MG, Mittal BR, and Shukla J
- Subjects
- Animals, Humans, Rats, Tissue Distribution, Female, Neoplasms diagnostic imaging, Neoplasms drug therapy, Integrin alphaVbeta3 metabolism, Integrin alphaVbeta3 antagonists & inhibitors, Peptidomimetics pharmacology, Peptidomimetics pharmacokinetics, Radiopharmaceuticals pharmacokinetics, Radiopharmaceuticals pharmacology, Rats, Wistar
- Abstract
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 (Kd ) 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%). Kd and Bmax 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 (SUVmax ) of 3.94 ± 0.58 compared with [18 F]FDG (SUVmax 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.- Published
- 2024
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