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European Journal of Nuclear Medicine and Molecular Imaging

Published in:

01-10-2021 | Original Article

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

Authors: Narges K. Tafreshi, Darpan N. Pandya, Christopher J. Tichacek, Mikalai M. Budzevich, Zhen Wang, Jordan N. Reff, Robert W. Engelman, David C. Boulware, Alberto A. Chiappori, Jonathan R. Strosberg, Haitao Ji, Thaddeus J. Wadas, Ghassan El-Haddad, David L. Morse

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 11/2021

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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Title: Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms
Authors: Narges K. Tafreshi
Darpan N. Pandya
Christopher J. Tichacek
Mikalai M. Budzevich
Zhen Wang
Jordan N. Reff
Robert W. Engelman
David C. Boulware
Alberto A. Chiappori
Jonathan R. Strosberg
Haitao Ji
Thaddeus J. Wadas
Ghassan El-Haddad
David L. Morse
Publication date: 01-10-2021
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 11/2021
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-021-05315-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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