Journal article
Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms
European journal of nuclear medicine and molecular imaging, Vol.48(11), pp.3408-3421
10/2021
DOI: 10.1007/s00259-021-05315-1
PMID: 33772332
Abstract
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
Lu ([
Lu]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 [
Ac]Ac-DOTA-TATE in patients that were refractory to [
Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [
Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs).
[
Ac]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 [
Ac]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data.
[
Ac]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 [
Ac]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
Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [
Ac]Ac-DOTA-TATE relative to controls.
These results suggest significant potential for the clinical translation of [
Ac]Ac-DOTA-TATE for lung NENs.
Details
- Title: Subtitle
- Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms
- Creators
- Narges K Tafreshi - Moffitt Cancer CenterDarpan N Pandya - University of IowaChristopher J Tichacek - University of South FloridaMikalai M BudzevichZhen Wang - Moffitt Cancer CenterJordan N Reff - Moffitt Cancer CenterRobert W Engelman - University of South FloridaDavid C Boulware - Moffitt Cancer CenterAlberto A Chiappori - Moffitt Cancer CenterJonathan R Strosberg - Moffitt Cancer CenterHaitao Ji - Moffitt Cancer CenterThaddeus J Wadas - University of IowaGhassan El-Haddad - Moffitt Cancer CenterDavid L Morse - Moffitt Cancer Center
- Resource Type
- Journal article
- Publication Details
- European journal of nuclear medicine and molecular imaging, Vol.48(11), pp.3408-3421
- DOI
- 10.1007/s00259-021-05315-1
- PMID
- 33772332
- ISSN
- 1619-7070
- eISSN
- 1619-7089
- Grant note
- DOI: 10.13039/100009863, name: Neuroendocrine Tumor Research Foundation; DOI: 10.13039/100005567, name: H. Lee Moffitt Cancer Center and Research Institute; DOI: 10.13039/100000054, name: National Cancer Institute, award: P30-CA076292
- Language
- English
- Date published
- 10/2021
- Academic Unit
- Radiology; Radiation Oncology
- Record Identifier
- 9984313072802771
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