Daneng Li1, Megan Minnix2, Rebecca Allen1, James Bading1, Junie Chea3, Patty Wong2, Nicole Bowles3, Erasmus Poku3, John E Shively2. 1. Department of Medical Oncology, City of Hope National Medical Center, Duarte, California, USA. 2. Deparment of Molecular Imaging and Therapy, Beckman Research Institute of City of Hope, Duarte, California, USA. 3. Radiopharmacy, Beckman Research Institute of the City of Hope, Duarte, California, USA.
Abstract
Background: The aim of the study was to perform PET imaging and radiotherapy with a novel neurotensin derivative for neurotensin receptor 1 (NTSR-1)-positive tumors in an animal model. Materials and Methods: A di-DOTA analog of NT(6-13) with three unnatural amino acids was synthesized and radiolabeled with either 64Cu or 68Ga and tested for serum stability and tumor imaging in mice bearing NTSR-1-positive PC3, and HT29 xenografts. A dose-response therapy study was performed with 18.5, 37, and 74 kBq of 225Ac-di-DOTA-α,ɛ-Lys-NT(6-13). Results: 68Ga-di-DOTA-α,ɛ-Lys-NT(6-13) was >99% stable in serum for 48 h, had an IC50 of 5 nM using 125I labeled NT(8-13) for binding to HT-29 cells, and high uptake in tumor models expressing NTSR-1. 68Ga-di-DOTA-α,ɛ-Lys-NT(6-13) had an average %ID/g (n = 4) at 2 h of 4.0 for tumor, 0.5 for blood, 12.0 for kidney, and <1 for other tissues, resulting in a favorable T/B of 8. Mean survivals of tumor-bearing mice treated with 18.5 or 37 kBq of 225Ac-di-DOTA-α,ɛ-Lys-NT(6-13) were 81 and 93 d, respectively, versus 53 d for controls. Whole-body toxicity was seen for the 74 kBq dose. Conclusions: Based on the results of the animal model, di-DOTA-α,ɛ-Lys-NT(6-13) is a useful imaging agent for NTSR-1-positive tumors when radiolabeled with 68Ga, and when radiolabeled with 225Ac, a potent therapeutic agent.
Background: The aim of the study was to perform PET imaging and radiotherapy with a novel neurotensin derivative for neurotensin receptor 1 (NTSR-1)-positive tumors in an animal model. Materials and Methods: A di-DOTA analog of NT(6-13) with three unnatural amino acids was synthesized and radiolabeled with either 64Cu or 68Ga and tested for serum stability and tumor imaging in mice bearing NTSR-1-positive PC3, and HT29 xenografts. A dose-response therapy study was performed with 18.5, 37, and 74 kBq of 225Ac-di-DOTA-α,ɛ-Lys-NT(6-13). Results: 68Ga-di-DOTA-α,ɛ-Lys-NT(6-13) was >99% stable in serum for 48 h, had an IC50 of 5 nM using 125I labeled NT(8-13) for binding to HT-29 cells, and high uptake in tumor models expressing NTSR-1. 68Ga-di-DOTA-α,ɛ-Lys-NT(6-13) had an average %ID/g (n = 4) at 2 h of 4.0 for tumor, 0.5 for blood, 12.0 for kidney, and <1 for other tissues, resulting in a favorable T/B of 8. Mean survivals of tumor-bearing mice treated with 18.5 or 37 kBq of 225Ac-di-DOTA-α,ɛ-Lys-NT(6-13) were 81 and 93 d, respectively, versus 53 d for controls. Whole-body toxicity was seen for the 74 kBq dose. Conclusions: Based on the results of the animal model, di-DOTA-α,ɛ-Lys-NT(6-13) is a useful imaging agent for NTSR-1-positive tumors when radiolabeled with 68Ga, and when radiolabeled with 225Ac, a potent therapeutic agent.
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