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

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

doi:10.1007/s00259-021-05315-1

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

Eur J Nucl Med Mol Imaging. 2021 Oct;48(11):3408-3421. doi: 10.1007/s00259-021-05315-1. Epub 2021 Mar 26.

Authors

Narges K Tafreshi¹, Darpan N Pandya², Christopher J Tichacek^{3

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 Morse^{13

14

15

16}

Affiliations

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.

PMID: 33772332
DOI: 10.1007/s00259-021-05315-1

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.

Keywords: 225Ac targeted alpha therapy; Lung neuroendocrine neoplasms; [225Ac]Ac-DOTA-TATE.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

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

Substances

Organometallic Compounds
Radiopharmaceuticals
Octreotide