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Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms

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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.

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Acknowledgements

Animal studies were conducted in the Moffitt Vivarium administered by the University of South Florida. The Analytic Microscopy, Bioinformatics and Biostatistics, Small Animal Imaging Laboratory and Tissue Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute provided support. Actinium-225 was supplied by the United States Department of Energy Office of Science Isotope Program in the Office of Nuclear Physics.

Funding

Funding was provided by the Neuroendocrine Tumor Research Foundation (Morse, El-Haddad), the Moffitt Radiology Pilot Award (El-Haddad, Morse), and the Moffitt NET Research Fund (El Haddad, Strosberg). The Analytic Microscopy, Bioinformatics and Biostatistics, Small Animal Imaging Laboratory and Tissue Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute an NCI designated Comprehensive Cancer Center (P30-CA076292) provided support.

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Authors and Affiliations

  1. Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Narges K. Tafreshi, Jordan N. Reff & David L. Morse

  2. Department of Radiology, University of Iowa Health Care, Iowa City, IA, USA

    Darpan N. Pandya & Thaddeus J. Wadas

  3. Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Christopher J. Tichacek

  4. Department of Physics and Oncologic Sciences, University of South Florida, Tampa, FL, USA

    Christopher J. Tichacek & David L. Morse

  5. Oncologic Sciences, University of South Florida, Tampa, FL, USA

    Christopher J. Tichacek & David L. Morse

  6. Small Animal Imaging Laboratory Shared Resource, Tampa, FL, USA

    Mikalai M. Budzevich & David L. Morse

  7. Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Zhen Wang & Haitao Ji

  8. Department of Pediatrics, Pathology & Cell Biology, University of South Florida, Tampa, FL, USA

    Robert W. Engelman

  9. Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    David C. Boulware

  10. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Alberto A. Chiappori

  11. Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Jonathan R. Strosberg

  12. Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Ghassan El-Haddad

Authors
  1. Narges K. Tafreshi
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  2. Darpan N. Pandya
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  3. Christopher J. Tichacek
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  4. Mikalai M. Budzevich
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  5. Zhen Wang
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  6. Jordan N. Reff
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  7. Robert W. Engelman
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  9. Alberto A. Chiappori
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  10. Jonathan R. Strosberg
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  11. Haitao Ji
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  12. Thaddeus J. Wadas
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  13. Ghassan El-Haddad
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  14. David L. Morse
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Contributions

Drs. Morse and El-Haddad are the corresponding authors and principal investigators that initiated and led the coordination, planning, and execution of the multi-institutional and multi-disciplinary studies reported herein. Dr. Wadas planned, led, and conducted the radiochemistry at University of Iowa. Dr. Tafreshi contributed to the planning and coordination of the biological studies conducted at Moffitt. Dr. Tafreshi also prepared the first draft of the manuscript. Dr. Pandya performed the radiochemistry at University of Iowa. Drs. Tichacek and Budzevich participated in activity measurements, biodistribution data analyses, and radiation dosimetry calculations. Jordan Reff contributed to the animal studies at Moffitt. Dr. Engelman performed the pathology analyses for the toxicity studies at Moffitt. Drs. Ji and Wang performed the lanthanum and europium chelations. David Boulware performed statistical analyses. Drs. Chiappori and Dr. Strosberg advised regarding the clinical perspective and clinical aspects of this work.

Corresponding authors

Correspondence to Ghassan El-Haddad or David L. Morse.

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Conflict of interest

Drs. Morse and Wadas are co-inventors on a provisional patent application. No other potential conflicts of interest relevant to this article exist.

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Tafreshi, N.K., Pandya, D.N., Tichacek, C.J. et al. Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms. Eur J Nucl Med Mol Imaging 48, 3408–3421 (2021). https://doi.org/10.1007/s00259-021-05315-1

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