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

Abstract

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 beta-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 degrees C, demonstrated the release of less than 15% of the activity within three half-lives. The biodistribution of Re-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.

Mixed-ligand complexes of yttrium-90 dialkyldithiocarbamates with 1,10-phenanthroline as a possible agent for therapy of hepatocellular carcinoma

“…Lipophilicity can easily be modified by modulating the length of the alkyl chain. Several radiopharmaceutical complexes have been described with dithiocarbamates, with indium-113m (Abram et al, 1985), copper-62 (Matsumoto et al, 1990), bismuth-212 (Parks et al, 1992), technetium-99m (Pasqualini et al, 1994), and rhenium-188 (Boschi et al, 2004). Moreover, rare earth complexes with dithiocarbamates have been the subject of an abundant literature and their structures have been extensively discussed (Nief, 1998;Cotton, 2004;Hitchcock et al, 2004;Regulacio et al, 2005).…”

Defining Pharmacokinetics for Individual Patient Dosimetry in Routine Radiopeptide and Radioimmunotherapy of Cancer: Australian Experience

“…We attempted to perform prospective individualized dosimetry on a prior tracer activity of 188 Re-lipiodol with quantitative gamma imaging immediately following non-selective intrahepatic arterial administration under direct radiographic guidance. Although the 188 Re-lipiodol is accumulated preferentially by HCC tumours and the degree of lung uptake is less than that seen with 131 I-lipiodol [28] the viscous oily lipiodol profoundly affects the regional distribution of blood flow in the hepatic arterial circulation.…”

“…Hepatocellular carcinoma (HCC) is the commonest cause of death from cancer throughout Asia and the advent of the 188 W/ 188 Re generator has facilitated practical, affordable inhouse preparation of 188 Re-lipiodol for intrahepatic arterial therapy of both primary HCC and hepatic metastases in developing countries [28]. The recent IAEA-sponsored multicentre international clinical trial conducted in countries with high incidence of HCC using empiric administered activities showed proof-of-principle for safe, effective locoregional radionuclide therapy with 188 Re-lipiodol [29].…”

Rhenium-188 Production in Hospitals, by W-188/Re-188 Generator, for Easy Use in Radionuclide Therapy

“…However, the labeled yield is rather small (50%–70%) and thus the possibility to achieve high therapeutic activity is limited. For that reason a number of studies [11–15] have focused on the development of new radiopharmaceuticals with high yield. These include Re-188 N-DEDC, Re-188-SSS Lipiodol, and Re-188 human serum albumin or HSA B20 microspheres (range  15–37 m).…”