Narges K Tafreshi1, Darpan N Pandya2, Christopher J Tichacek3,4,5, Mikalai M Budzevich6, Zhen Wang7, Jordan N Reff1, Robert W Engelman8, David C Boulware9, Alberto A Chiappori10, Jonathan R Strosberg11, Haitao Ji7, Thaddeus J Wadas2, Ghassan El-Haddad12, David L Morse13,14,15,16. 1. Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. 2. Department of Radiology, University of Iowa Health Care, Iowa City, IA, USA. 3. Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. 4. Department of Physics and Oncologic Sciences, University of South Florida, Tampa, FL, USA. 5. Oncologic Sciences, University of South Florida, Tampa, FL, USA. 6. Small Animal Imaging Laboratory Shared Resource, Tampa, FL, USA. 7. Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. 8. Department of Pediatrics, Pathology & Cell Biology, University of South Florida, Tampa, FL, USA. 9. Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. 10. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. 11. Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. 12. Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. Ghassan.ElHaddad@moffitt.org. 13. Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. David.Morse@moffitt.org. 14. Department of Physics and Oncologic Sciences, University of South Florida, Tampa, FL, USA. David.Morse@moffitt.org. 15. Oncologic Sciences, University of South Florida, Tampa, FL, USA. David.Morse@moffitt.org. 16. Small Animal Imaging Laboratory Shared Resource, Tampa, FL, USA. David.Morse@moffitt.org.
Abstract
PURPOSE: There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the β-particle emitting radionuclide 177Lu ([177Lu]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [225Ac]Ac-DOTA-TATE in patients that were refractory to [177Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [225Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). METHODS: [225Ac]Ac-DOTA-TATE was synthesized and characterized for radiochemical yield, purity and stability. Non-tumor-bearing BALB/c mice were tested for toxicity and BD. Efficacy was determined by single intravenous injection of [225Ac]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. RESULTS: [225Ac]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2 days incubation in human serum at 37 °C. All animals in the toxicity study appeared healthy 5 months post injection with no indications of toxicity, except that animals that received ≥111 kBq of [225Ac]Ac-DOTA-TATE had chronic progressive nephropathy. BD studies revealed that the primary route of elimination is by the renal route. RD calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [225Ac]Ac-DOTA-TATE relative to controls. CONCLUSIONS: These results suggest significant potential for the clinical translation of [225Ac]Ac-DOTA-TATE for lung NENs.
PURPOSE: There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the β-particle emitting radionuclide 177Lu ([177Lu]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [225Ac]Ac-DOTA-TATE in patients that were refractory to [177Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [225Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). METHODS: [225Ac]Ac-DOTA-TATE was synthesized and characterized for radiochemical yield, purity and stability. Non-tumor-bearing BALB/c mice were tested for toxicity and BD. Efficacy was determined by single intravenous injection of [225Ac]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. RESULTS: [225Ac]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2 days incubation in human serum at 37 °C. All animals in the toxicity study appeared healthy 5 months post injection with no indications of toxicity, except that animals that received ≥111 kBq of [225Ac]Ac-DOTA-TATE had chronic progressive nephropathy. BD studies revealed that the primary route of elimination is by the renal route. RD calculations determined pharmacokinetics parameters and absorbed α-emission dosages from 225Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [225Ac]Ac-DOTA-TATE relative to controls. CONCLUSIONS: These results suggest significant potential for the clinical translation of [225Ac]Ac-DOTA-TATE for lung NENs.
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