A kit formulation for the preparation of ¹⁸⁸Re-lipiodol: Preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma

A lyophilized kit formulation for the efficient labelling of lipiodol with generator-produced rhenium-188 is described. The preliminary preparation of the lipophilic complex bis-(diethyldithiocarbamato)nitrido rhenium-188 ( ¹⁸⁸ReN-DEDC) was carried out using a two-vial kit containing S-methyl-N-methyl-dithiocarbazate, SnCl₂ and sodium oxalate in the first vial, and diethyldithiocarbamate and a carbonate buffer in the second vial. After mixing of the reaction solution with lipiodol, the complex ¹⁸⁸ReN-DEDC was quantitatively extracted and retained by this hydrophobic substance, thus allowing the stable incorporation of the β-emitting radionuclide. The radiochemical purity of the complex ¹⁸⁸ReN-DEDC was 97 ± 2%. The activity extracted into the lipiodol phase was 96 ± 3% of the initial activity, indicating that the complex ¹⁸⁸ReN-DEDC was almost quantitatively removed from the aqueous reaction solution. In vitro stability studies in human plasma, at 37°C, demonstrated the release of less than 15% of the activity within three half-lives. The biodistribution of ¹⁸⁸Re-lipiodol in non-tumour-bearing Wistar rats at 6, 24, 48 and 72 h after intraportal venous injection showed one-third of total activity in the liver at 6 h, declining to 2% retention at 72 h. Bowel uptake at 6 and 24 h declined to low levels at 48 and 72 h. Renal activity peaked at 1.7%, diminishing to 0.6% over 48 h. Rat whole body gamma imaging showed gut activity in addition to hepatic uptake at 6 and 24 h, but only liver was evident from 48 to 72 h. Kidneys were not demonstrable at any imaging time point. In nine patients, activity was localized in the tumours immediately following intrahepatic arterial injection. Computed tomography/single-photon emission computed tomography (CT/SPECT) imaging at 1 and 24 h confirmed the retention of ¹⁸⁸Re-lipiodol in the hepatoma, with minimal gut uptake and no lung activity over 24 h. These patients were subsequently treated with activities of 2.5-5 GBq of ¹⁸⁸Re-lipiodol fractions without adverse effects. Six patients followed for up to 2 years in the pilot study achieved stable disease and there was objective partial response in one patient. Repeated treatments were performed on two to three occasions in three patients without evident toxicity. An additional patient given 6 GBq of ¹⁸⁸Re-lipiodol demonstrated myelosuppression, which recovered with granulocyte colony-stimulating factor (GCSF) and platelet support. It is concluded that ¹⁸⁸Re-lipiodol, prepared using our novel kit formulation, is stable in vivo and provides safe and effective therapy of unresectable hepatocellular carcinoma when given via the hepatic artery, either alone or in combination with transarterial chemoembolization.