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

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.

• 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
• Journal: European journal of nuclear medicine and molecular imaging (Eur J Nucl Med Mol Imaging) Vol. 48 Issue 11 Pg. 3408-3421 (10 2021) ISSN: 1619-7089 [Electronic] Germany
• PMID: 33772332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Organometallic Compounds
• Radiopharmaceuticals
• Octreotide

Topics

• Animals
• Humans
• Lung Neoplasms (drug therapy)
• Mice
• Mice, Inbred BALB C
• Mice, SCID
• Octreotide (therapeutic use, toxicity)
• Organometallic Compounds (therapeutic use, toxicity)
• Radiopharmaceuticals (therapeutic use, toxicity)
• Tissue Distribution