Evaluation of Candidate Theranostics for 227Th/89Zr Paired Radioimmunotherapy of Lymphoma.

227Th is a promising radioisotope for targeted α-particle therapy. It produces 5 α-particles through its decay, with the clinically approved 223Ra as its first daughter. There is an ample supply of 227Th, allowing for clinical use; however, the chemical challenges of chelating this large tetravalent f-block cation are considerable. Using the CD20-targeting antibody ofatumumab, we evaluated chelation of 227Th4+ for α-particle-emitting and radiotheranostic applications. Methods: We compared 4 bifunctional chelators for thorium radiopharmaceutical preparation: S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2-(4-isothicyanatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (p-SCN-Bn-HEHA), p-isothiacyanatophenyl-1-hydroxy-2-oxopiperidine-desferrioxamine (DFOcyclo*-p-Phe-NCS), and macrocyclic 1,2-HOPO N-hydroxysuccinimide (L804-NHS). Immunoconstructs were evaluated for yield, purity, and stability in vitro and in vivo. Tumor targeting of the lead 227Th-labeled compound in vivo was performed in CD20-expressing models and compared with a companion 89Zr-labeled PET agent. Results: 227Th-labeled ofatumumab-chelator constructs were synthesized to a radiochemical purity of more than 95%, excepting HEHA. 227Th-HEHA-ofatumumab showed moderate in vitro stability. 227Th-DFOcyclo*-ofatumumab presented excellent 227Th labeling efficiency; however, high liver and spleen uptake was revealed in vivo, indicative of aggregation. 227Th-DOTA-ofatumumab labeled poorly, yielding no more than 5%, with low specific activity (0.08 GBq/g) and modest long-term in vitro stability (<80%). 227Th-L804-ofatumumab coordinated 227Th rapidly and efficiently at high yields, purity, and specific activity (8 GBq/g) and demonstrated extended stability. In vivo tumor targeting confirmed the utility of this chelator, and the diagnostic analog, 89Zr-L804-ofatumumab, showed organ distribution matching that of 227Th to delineate SU-DHL-6 tumors. Conclusion: Commercially available and novel chelators for 227Th showed a range of performances. The L804 chelator can be used with potent radiotheranostic capabilities for 89Zr/227Th quantitative imaging and α-particle therapy.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Improved Radium-223 Therapy with Combination Epithelial Sodium Channel Blockade.

Background: Radium-223 dichloride ([223Ra]RaCl2) is the first approved alpha particle-emitting therapy and is indicated for treatment of bone metastatic castrate resistant prostate cancer. Approximately half of the dose is absorbed into the gastrointestinal (GI) tract within minutes of administration, limiting disease-site uptake and contributing to toxicity. Here, we investigate the role of enteric ion channels and their modulation for improved therapeutic efficacy and reduced side effects. Methods: Utilizing primary human duodenal organoids (enteroids) as in vitro models of the functional GI epithelium, we found that Amiloride (ENaC blocker) and NS-1619 (K+ channel activator) presented significant effects in 223Ra membranal transport. The radioactive drug distribution was evaluated for lead combinations in vivo, and in osteosarcoma and prostate cancer models. Results: Amiloride shifted 223Ra uptake in vivo from the gut, to nearly double the uptake at sites of bone remodeling. Bone tumor growth inhibition with the combination as measured by bioluminescent and X-ray imaging was significantly greater than single agents alone, and the combination resulted in no weight loss. Conclusion: This combination of approved agents may be readily implemented as a clinical approach to improve outcomes of bone metastatic cancer patients with the benefit of ameliorated tolerability.