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

• Published in: European journal of nuclear medicine and molecular imaging 2021-10, Vol.48 (11), p.3408-3421
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-021-05315-1

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.