Ac-EAZY! Towards GMP-Compliant Module Syntheses of 225Ac-Labeled Peptides for Clinical Application

Abstract

The application of 225Ac (half-life T1/2 = 9.92 d) dramatically reduces the activity used for peptide receptor radionuclide therapy by a factor of 1000 in comparison to 90Y, 177Lu or 188Re while maintaining the therapeutic outcome. Additionally, the range of alpha particles of 225Ac and its daughter nuclides in tissue is much lower (47–85 μm for alpha energies Eα = 5.8–8.4 MeV), which results in a very precise dose deposition within the tumor. DOTA-conjugated commercially available peptides used for endoradiotherapy, which can readily be labeled with 177Lu or 90Y, can also accommodate 225Ac. The benefits are lower doses in normal tissue for the patient, dose reduction of the employees and environment and less shielding material. The low availability of 225Ac activity is preventing its application in clinical practice. Overcoming this barrier would open a broad field of 225Ac therapy. Independent which production pathway of 225Ac proves the most feasible, the use of automated synthesis and feasible and reproducible patient doses are needed. The Modular-Lab EAZY is one example of a GMP-compliant system, and the cassettes used for synthesis are small. Therefore, also the waste after the synthesis can be minimized. In this work, two different automated setups with different purification systems are presented. In its final configuration, three masterbatches were performed on the ML EAZY for DOTA-TATE and PSMA-I&T, respectively, fulfilling all quality criteria with final radiochemical yields of 80–90% for the 225Ac-labeled peptides.

Gamma counting protocols for the accurate quantification of 225Ac and 213Bi without the need for a secular equilibrium between parent and gamma-emitting daughter

“…Therefore, we suggested a single GC measurement to determine the 225 Ac activity using the EW of 221 Fr. This can be done once SEq is established between 225 Ac and 221 Fr around 30 min after mixed 225 Ac/ 213 Bi samples have been synthetized as was previously reported (Hooijman et al 2021 ; Pretze et al 2021 ). However, we noticed that 225 Ac activity estimated with the EW of 221 Fr is biased when the activity of 213 Bi does not correspond with the expected activity in case of SEq with 225 Ac.…”

Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists

“…Macropa, crown, and py4pa are new chelators with improved radiochemical yield and specific activity, as well as achievable labeling conditions. However, none of the new chelators was investigated enough so far to confirm in vivo stability, and their potential to translate into clinical application is yet to be assessed (118)(119)(120)(121)(122).…”

“…This can typically be differentiated in a gamma spectrometer by splitting the plate. Fr-221 has a line at 218 keV and Bi-213 at 440 keV ( 122 , 124 ). However, the measurement with radio-TLC is not a valid method to determine the yield and purity of a radiopharmaceutical and additional radio-HPLC methods are required.…”

A Review of 177Lutetium-PSMA and 225Actinium-PSMA as Emerging Theranostic Agents in Prostate Cancer

“…In addition, the high energy of alpha particles, which may be many MeV, along with the strong linear energy transfer that comes with it, causes a significant increase in the number of cells killed. As a consequence, alpha radiation can kill cells that, under normal circumstances, would be resistant to treatment with beta or gamma irradiation or chemotherapeutic drugs, hence making alpha radiation a viable treatment option for tumors that are resistant to conventional therapies [ 50 ] (Figure 2 ).…”