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; Engelman, Robert W.; Boulware, David; Chiappori, Alberto; Strosberg, Jonathan R.; Ji, Haitao; Wadas, Thaddeus J.; El-Haddad, Ghassan; Morse, David L.

doi:10.1007/s00259-021-05315-1

Cited by 26 publications

(18 citation statements)

References 37 publications

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“…4–7). 225 Ac-MACROPATATE and 225 Ac-DOTATATE were stable to 10 d. Stability experiments conducted in human serum indicated that 225 Ac-MACROPATATE has significantly greater stability than 225 Ac-DOTATATE (98% vs. 95%, P = 0.0097), and our results compared well with a recent stability investigation of 225 Ac-DOTATATE reported by others, which found 90% intact 225 Ac-DOTATATE after 10 d ( 27 ). Thus, 225 Ac-MACROPATATE exhibited a modest yet significant stability advantage over 225 Ac-DOTATATE.…”

Section: Resultssupporting

confidence: 90%

“…Saturation binding assays showed a binding affinity of 21 nM ( Fig. 2D ), comparable to that reported for Eu-DOTATATE (22 nM), which has been used as a surrogate for 225 Ac-labeled DOTATATE ( 27 ). This value is also in a similar range to other studies examining radiopeptide somatostatin derivatives ( 31 , 32 ).…”

Section: Resultssupporting

confidence: 81%

“…Mice ( n ≥ 3) bearing H69 tumor xenografts were first injected with d -lysine hydrochloride (35 mg/mouse) and then treated with 148, 93.3, 46.3, or 23.1 kBq of 225 Ac-MACROPATATE; their body weights and tumor growth were monitored over several weeks. The highest tested dose of 225 Ac-MACROPATATE was based on a recent report of therapy using 225 Ac-DOTATATE, which found that 148 kBq was well tolerated in mice ( 27 ).…”

Section: Methodsmentioning

confidence: 99%

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²²⁵Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

et al. 2022

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

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²²⁵Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

et al. 2022

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“…More recently, the challenge of tumor radioresistance triggered the concept of targeted α-therapy, which is particularly effective due to the high linear energy transfer (LET) of α-particles (50-230 keV/μm) [13][14][15]. PRRT using [ 213 Bi]Bi-DOTATOC or [ 225 Ac]Ac-DOTATATE in patients, refractory to 90 Y-and/or 177 Lu-based PRRT, resulted in partial remission or stable disease [16,17].…”

Section: Introductionmentioning

confidence: 99%

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Borgna

Haller

Rodríguez

et al. 2021

Eur J Nucl Med Mol Imaging

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Purpose The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs.

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“…At present, the dosimetry assessment for 225 Ac-(prostate specific membrane antigen) PSMA-617 is anticipated on account of time-activity curves (TAC) derived from 177 Lu-PSMA-617 sequential imaging [51]. Dosimetry of 225 Ac radiopharmaceuticals based on medical internal radiation dosimetry general model for alpha particles has been reported in animal models [52][53][54]. Micro-dosimetry originally introduced by Rossi et al [55] for the calculation of energy deposition by external ionizing radiation can also be used to determine the energy deposited by alpha particles internally [55,56].…”

Section: Dosimetry Of 225 Ac Radiopharmaceuticalsmentioning

confidence: 99%

Challenges and opportunities in developing Actinium-225 radiopharmaceuticals

Dhiman

Vatsa

Sood

2022

Nuclear Medicine Communications

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Actinium-225 ( 225 Ac) has emerged as a promising therapeutic radioisotope for targeted alpha therapy. It emits net four alpha particles during its decay to stable daughter bismuth-209, rightly called an in-vivo nanogenerator. Compared to the worldwide demand of 225 Ac, the amount produced via depleted thorium-229 sources is minimal, making it an expensive radionuclide. However, many research groups are working on optimizing the parameters for the production of 225 Ac via different routes, including cyclotrons, reactors and high-energy linear accelerators. The present review article focuses on the various aspects associated with the development of 225 Ac radiopharmaceuticals. It includes the challenges and opportunities associated with the production methods, labeling chemistry, in-vivo kinetics and dosimetry of 225 Ac radiopharmaceuticals. A brief description is also given about the 225 Ac radiopharmaceuticals at preclinical stages, clinical trials and used routinely.

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

Cited by 26 publications

References 37 publications

²²⁵Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

²²⁵Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Challenges and opportunities in developing Actinium-225 radiopharmaceuticals

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

Cited by 26 publications

References 37 publications

225Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

225Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Challenges and opportunities in developing Actinium-225 radiopharmaceuticals

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Product

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²²⁵Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

²²⁵Ac-MACROPATATE: A Novel α-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors