Clinical translation of a novel dual integrin αvβ3 and GRPR targeting PET radiotracer 68Ga-NOTA-BBN-RGD
Jingling Zhang, Peking Union Medical College Hospital (PUMCH); National Institutes of Health
Objective: This study aims to document the first-in-human application of a 68Ga-labeled-heterodimeric peptide BBN-RGD that targets both integrin αvβ3 and gastrin releasing peptide receptor (GRPR). We evaluated the safety, calculated the radiation dose, and assessed the clinical diagnostic value in tumors.
Methods: A macrocyclic chelator, 1,4,7-triazacyclononane-N,N’,N”-triacetic acid (NOTA) conjugated BBN-RGD was synthesized and labeled with 68Ga. The quality control was performed with analytical HPLC and TLC. After the clinical protocol was approved by the institute review board, five healthy volunteers (M 4, F 1, 28–53 y) were enrolled to validate the safety of 68Ga-NOTA-BBN-RGD. A total of 27 cancer patients including 15 prostate cancer, 5 glioma, 3 gastrointestinal tumor, 2 lung cancer and 2 pancreatic cancer patients with written informed consent were recruited. All the recruited patients underwent PET/CT scans 30–45 min after intravenous injection of 92.5-129.5 MBq (2.5–3.5 mCi) of 68Ga-NOTA-BBN-RGD, and also accepted 68Ga-NOTA-BBN and/or 68Ga-NOTA-PRGD2 PET/CT within 2 weeks for comparison.
RESULTS: The whole labeling process of 68Ga-NOTA-BBN-RGD took about 30 min with a radiochemical purity of greater than 95%. For this first-in-human study in healthy volunteers with a mean injected dose of 2.9 ± 0.4 mCi, no side effect was found during the whole procedure and 2 weeks follow-up, demonstrating the safety of 68Ga-NOTA-BBN-RGD. A patient would be exposed to a radiation dose of 2.21 mSv with an injected dose of 2.5-3.5 mCi (92.5-129.5 MBq), which is much lower than the dose limit as set by the FDA. 68Ga-NOTA-BBN-RGD PET/CT detected both the primary prostate cancer in 2 newly diagnosed by the biopsy and bone metastasis in 13 post-treatment patients, the average and maximum standard uptake values (SUVs) of all the 31 bone metastasis lesions were 2.87 ± 0.93 and 4.79 ± 1.57 at 30 min after injection respectively. The SUVavg and SUVmax in glioma patients (n = 5) at 30 min after injection of 68Ga-NOTA-BBN-RGD were 1.8 ± 1.1 and 3.2 ± 1.5 respectively, with low background and much lower choroid plexus uptake compared with 68Ga-NOTA-PRGD2. Moderate uptake of 68Ga-NOTA-BBN-RGD were demonstrated in 2 lung adenocarcinoma. For the gastrointestinal tumor, 68Ga-NOTA-BBN-RGD PET/CT detected primary, recurrent and metastasis lesions in 3 gastric and 1 colon cancer, which may be more specific than 18F-FDG PET/CT in assessing gastrointestinal tumor.
Conclusion: This study indicates the safety and the efficiency of a new PET radiotracer 68Ga-NOTA-BBN-RGD. This novel dual integrin αvβ3 and GRPR targeting PET radiotracer showed significant value in prostate cancer, glioma, lung cancer and gastrointestinal tumor diagnosis.
Keywords: BBN-RGD; PET; first-in-human; integrin αvβ3; GRPR
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