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

Alessandra Boschi, Licia Uccelli, Adriano Duatti, Paolo Colamussi, Corrado Cittanti, Angelina Filice, Alison H. Rose, Andrew A. Martindale, Paul G. Claringbold, Dermot Kearney, Roberto Galeotti, Harvey J. Turner, Melchiore Giganti

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)691-699
Number of pages9
JournalNuclear Medicine Communications
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 2004

Fingerprint

Ethiodized Oil
Hepatocellular Carcinoma
Rhenium
Therapeutics
Liver
Kidney
Ditiocarb
Whole Body Imaging
Oxalic Acid
Injections
Hepatic Artery
Carbonates
Granulocyte Colony-Stimulating Factor
Radioisotopes
Wistar Rats
Buffers
Blood Platelets
Lung

Keywords

  • Hepatocellular carcinoma
  • Lipiodol
  • Nitrido complexes
  • Rhenium-188

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

A kit formulation for the preparation of 188Re-lipiodol : Preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma. / Boschi, Alessandra; Uccelli, Licia; Duatti, Adriano; Colamussi, Paolo; Cittanti, Corrado; Filice, Angelina; Rose, Alison H.; Martindale, Andrew A.; Claringbold, Paul G.; Kearney, Dermot; Galeotti, Roberto; Turner, Harvey J.; Giganti, Melchiore.

In: Nuclear Medicine Communications, Vol. 25, No. 7, 07.2004, p. 691-699.

Research output: Contribution to journalArticle

Boschi, A, Uccelli, L, Duatti, A, Colamussi, P, Cittanti, C, Filice, A, Rose, AH, Martindale, AA, Claringbold, PG, Kearney, D, Galeotti, R, Turner, HJ & Giganti, M 2004, 'A kit formulation for the preparation of 188Re-lipiodol: Preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma', Nuclear Medicine Communications, vol. 25, no. 7, pp. 691-699. https://doi.org/10.1097/01.mnm.0000130241.22068.45
Boschi, Alessandra ; Uccelli, Licia ; Duatti, Adriano ; Colamussi, Paolo ; Cittanti, Corrado ; Filice, Angelina ; Rose, Alison H. ; Martindale, Andrew A. ; Claringbold, Paul G. ; Kearney, Dermot ; Galeotti, Roberto ; Turner, Harvey J. ; Giganti, Melchiore. / A kit formulation for the preparation of 188Re-lipiodol : Preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma. In: Nuclear Medicine Communications. 2004 ; Vol. 25, No. 7. pp. 691-699.
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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 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.",
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T1 - A kit formulation for the preparation of 188Re-lipiodol

T2 - Preclinical studies and preliminary therapeutic evaluation in patients with unresectable hepatocellular carcinoma

AU - Boschi, Alessandra

AU - Uccelli, Licia

AU - Duatti, Adriano

AU - Colamussi, Paolo

AU - Cittanti, Corrado

AU - Filice, Angelina

AU - Rose, Alison H.

AU - Martindale, Andrew A.

AU - Claringbold, Paul G.

AU - Kearney, Dermot

AU - Galeotti, Roberto

AU - Turner, Harvey J.

AU - Giganti, Melchiore

PY - 2004/7

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N2 - 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.

AB - 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.

KW - Hepatocellular carcinoma

KW - Lipiodol

KW - Nitrido complexes

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