Engineering a modular ⁴⁴Ti/⁴⁴Sc generator: eluate evaluation in preclinical models and estimation of human radiation...

⁴⁴Sc/⁴⁷Sc is an attractive theranostic pair for targeted in vivo positron emission tomographic (PET) imaging and beta-particle treatment of cancer. The ⁴⁴Ti/⁴⁴Sc generator allows daily onsite production of this diagnostic isotope, which may provide an attractive alternative for PET facilities that lack in-house irradiation capabilities. Early animal and patient studies have demonstrated the utility of ⁴⁴Sc. In our current study, we built and evaluated a novel clinical-scale ⁴⁴Ti/⁴⁴Sc generator, explored the pharmacokinetic profiles of ⁴⁴ScCl₃, [⁴⁴Sc]-citrate and [⁴⁴Sc]-NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) in naïve mice, and estimated the radiation burden of ⁴⁴ScCl₃ in humans.

⁴⁴Ti/⁴⁴Sc (101.2 MBq) in 6 M HCl solution was utilized to assemble a modular ZR resin containing generator. After assembly, ⁴⁴Sc was eluted with 0.05 M HCl for further PET imaging and biodistribution studies in female Swiss Webster mice. Based on the biodistribution data, absorbed doses of ^44/47ScCl₃ in human adults were calculated for 18 organs and tissues using the IDAC-Dose software.

⁴⁴Ti in 6 M HCl was loaded onto the organic resin generator with a yield of 99.97%. After loading and initial stabilization, ⁴⁴ScCl₃ was eluted with 0.05 M HCl in typical yields of 82.9 ± 5.3% (N = 16), which was normalized to the estimated generator capacity. Estimated generator capacity was computed based on elution time interval and the total amount of ⁴⁴Ti loaded on the generator. Run in forward and reverse directions, the ⁴⁴Sc/⁴⁴Ti ratio from a primary column was significantly improved from 1038 ± 440 to 3557 ± 680 (Bq/Bq) when a secondary, replaceable, ZR resin cartridge was employed at the flow outlet. In vivo imaging and ex vivo distribution studies of the reversible modular generator for ⁴⁴ScCl₃, [⁴⁴Sc]-citrate and [⁴⁴Sc]-NODAGA show that free ⁴⁴Sc remained in the circulation significantly longer than the chelated ⁴⁴Sc. The dose estimation of ⁴⁴ScCl₃ reveals that the radiation burden is 0.146 mSv/MBq for a 70 kg adult male and 0.179 mSv/MBq for a 57 kg adult female. Liver, spleen and heart wall will receive the highest absorbed dose: 0.524, 0.502, and 0.303 mGy/MBq, respectively, for the adult male.

A clinical-scale ⁴⁴Ti/⁴⁴Sc generator system with a modular design was developed to supply ⁴⁴ScCl₃ in 0.05 M HCl, which is suitable for further radiolabeling and in vivo use. Our data demonstrated that free ⁴⁴ScCl₃ remained in the circulation for extended periods, which resulted in approximately 10 times greater radiation burden than stably chelated ⁴⁴Sc. Stable ⁴⁴Sc/⁴⁷Sc-complexation will be more favorable for in vivo use and for clinical utility.