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

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

European journal of nuclear medicine and molecular imaging, 2021-10, Vol.48 (11), p.3408-3421 [Periódico revisado por pares]

Berlin/Heidelberg: Springer Berlin Heidelberg

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Título:
Preclinical evaluation of [225Ac]Ac-DOTA-TATE for treatment of lung neuroendocrine neoplasms
Autor: Tafreshi, Narges K. ; Pandya, Darpan N. ; Tichacek, Christopher J. ; Budzevich, Mikalai M. ; Wang, Zhen ; Reff, Jordan N. ; Engelman, Robert W. ; Boulware, David C. ; Chiappori, Alberto A. ; Strosberg, Jonathan R. ; Ji, Haitao ; Wadas, Thaddeus J. ; El-Haddad, Ghassan ; Morse, David L.
Assuntos: Alpha rays ; Animal models ; Animals ; Cardiology ; Dosimeters ; Dosimetry ; Humans ; Imaging ; Injection ; Intravenous administration ; Lung Neoplasms - drug therapy ; Lungs ; Lutetium isotopes ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Mice, SCID ; Neoplasia ; Neoplasms ; Nephropathy ; Neuroendocrine tumors ; Nuclear Medicine ; Octreotide - therapeutic use ; Octreotide - toxicity ; Oncology ; Organometallic Compounds - therapeutic use ; Organometallic Compounds - toxicity ; Original Article ; Orthopedics ; Pharmacokinetics ; Purity ; Radiochemistry ; Radioisotopes ; Radiology ; Radiopharmaceuticals - therapeutic use ; Radiopharmaceuticals - toxicity ; Route selection ; Solid tumors ; Somatostatin ; Somatostatin receptors ; Stability ; Synthesis ; Tissue Distribution ; Toxicity ; Toxicity testing ; Translational research ; Tumors
É parte de: European journal of nuclear medicine and molecular imaging, 2021-10, Vol.48 (11), p.3408-3421
Descrição: 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 177 Lu ([ 177 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 [ 225 Ac]Ac-DOTA-TATE in patients that were refractory to [ 177 Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [ 225 Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs). Methods [ 225 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 [ 225 Ac]Ac-DOTA-TATE into SCID mice–bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data. Results [ 225 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 [ 225 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 225 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 [ 225 Ac]Ac-DOTA-TATE relative to controls. Conclusions These results suggest significant potential for the clinical translation of [ 225 Ac]Ac-DOTA-TATE for lung NENs.
Editor: Berlin/Heidelberg: Springer Berlin Heidelberg
Idioma: Inglês

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

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

Berlin/Heidelberg: Springer Berlin Heidelberg

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