Abstract
BackgroundAs 225Ac-labeled radiopharmaceuticals continue to show promise as targeted alpha therapeutics, there is a growing need to standardize quality control (QC) testing procedures. The determination of radiochemical purity (RCP) is an essential QC test. A significant obstacle to RCP testing is the disruption of the secular equilibrium between actinium-225 and its daughter radionuclides during labeling and QC testing. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an 225Ac-labeled radiopharmaceutical can be accurately quantified.ResultsSix ligands were conjugated to macrocyclic metal chelators and labeled with actinium-225 under conditions designed to generate diverse incorporation yields. RCP was determined by radio thin layer chromatography (radioTLC) followed by exposure of the TLC plate on a phosphor screen either 0.5, 2, 3.5, 5, 6.5, or 26 h after the plate was developed. The dataset was used to create models for predicting the true RCP for any pre-equilibrium measurement taken at an early time point. The 585 TLC measurements span RCP values of 1.8–99.5%. The statistical model created from these data predicted an independent data set with high accuracy. Predictions made at 0.5 h are more uncertain than predictions made at later time points. This is primarily due to the decay of bismuth-213. A measurement of RCP > 90% at 2 h predicts a true RCP > 97% and guarantees that RCP will exceed 90% after secular equilibrium is reached. These findings were independently validated using NaI(Tl) scintillation counting and high resolution gamma spectroscopy on a smaller set of samples with 10% ≤ RCP ≤ 100%.ConclusionsRCP of 225Ac-labeled radiopharmaceuticals can be quantified with acceptable accuracy at least 2 h after radioTLC using various methods of quantifying particle emissions. This time point best balances the need to accurately quantify RCP with the need to safely release the batch as quickly as possible.
Highlights
Targeted alpha-particle therapy (TAT) shows great promise in the treatment of cancer most recently exemplified by the successful introduction of 223RaCl2 (Xofigo®) for the treatment of skeletal metastases (Nilsson et al 2005, 2012, 2016)
Radiolabeling experiments In order to generate a diverse range of radiochemical yields, reactions were performed using various chelators conjugated to a targeting vector, varying the concentration of the chelator–vector conjugate, and varying reaction time and temperature
Statistical modeling We developed a statistical model to predict the radiochemical purity (RCP) at secular equilibrium of any RCP measured at an early pre-equilibrium time point
Summary
Targeted alpha-particle therapy (TAT) shows great promise in the treatment of cancer most recently exemplified by the successful introduction of 223RaCl2 (Xofigo®) for the treatment of skeletal metastases (Nilsson et al 2005, 2012, 2016). Dramatic responses are even observed in patients refractory to beta-particle therapy (Kratochwil et al 2016). In addition to these small molecule radioligands, [225Ac]Ac-J591 is currently in Phase I clinical trials for radioimmunotherapy of prostate cancer (Tagawa et al 2018). Given these early and promising findings clinical investigations using actinium-225 TAT will likely continue to grow. In order to accelerate translation of actinium-225 targeted alpha therapy, we aimed to determine the earliest time point at which the RCP of an 225Ac-labeled radiopharma‐ ceutical can be accurately quantified
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