Valérie Ardisson

(188)Re-SSS/Lipiodol: Development of a Potential Treatment for HCC from Bench to Bedside.

Hepatocellular carcinoma (HCC) is the 5th most common tumour worldwide and has a dark prognosis. For nonoperable cases, metabolic radiotherapy with Lipiodol labelled with β-emitters is a promising therapeutic option. The Comprehensive Cancer Centre Eugène Marquis and the National Graduate School of Chemistry of Rennes (ENSCR) have jointly developed a stable and efficient labelling of Lipiodol with rhenium-188 (Eβmax = 2.1 MeV) for the treatment of HCC. The major “milestones” of this development, from the first syntheses to the recent first injection in man, are described.

Optimization of Hepatocarcinoma Uptake with Radiolabeled Lipiodol: Development of New Lipiodol Formulations with Increased Viscosity

The aim of this study was to develop new Lipiodol formulations with increased viscosities to augment Lipiodol embolic effect and optimize efficiency of radiolabeled Lipiodol in hepatocarcinoma treatments. New Lipiodol formulations consist of Lipiodol mixtures with different stearic acid concentrations (0.8%, 1.3%, and 1.8%). These formulations were fully characterized in vitro (viscosity, rheologic profiles) and labeled with 99mTc. Their viscosities at 20°C are 54, 60, and 67cP respectively, versus 45cP for Lipiodol ultra-fluide. Second, their biodistribution profiles were studied in vivo, at 24 and 72 hours, in hepatoma-bearing rats, and compared to control group (99mTc-Lipiodol). Biodistribution at 24 hours show a Gaussian tumor uptake profile with a maximum obtained with 1.3% stearic acid, and a tumor uptake superior to control group (+67%) (p<0.05). At 72 hours, optimal tumor uptake is reached with the 0.8% formulation, with 89% increase compared with control group (p<0.05). Moreover, we show a tendency to the decrease of pulmonary uptake for the new formulations at 24 hours and 72 hours. These results suggest a correlation between viscosity and Lipiodol tumor uptake. The new 0.8% stearic acid/Lipiodol formulation appears to be the optimized formulation for Lipiodol treatments of hepatocarcinoma, since it leads to a significant increase of tumor uptake at 72 hours and possibly to a decrease of undesirable pulmonary effects.

Looking for synergy or additivity between 188Re and sorafenib on hepatoma cell lines.

247 Background: In case of non resectable HCC, radioembolization and sorafenib (S) are therapeutic options respectively for intermediate and advanced stages. In some other cancers, there is an increase of efficacy when external beam radiotherapy is done concomitantly with systemic chemotherapy or targeted therapies. So we wondered if there could be a synergistic or an additive activity when S is combined with a radionuclide. METHODS Hepatoma cell lines N1S1 (murine HCC), HepG2 (human hepatoblastoma) and HepaRG (human HCC) were treated with increasing concentrations of rhenium-188 (188Re) or S. On each cell line, we have studied the cellular toxicities of S and 188Re using Tetrazolium dye test, extra-cellular medium LDH level and morphologic analysis. This was done for different dosage of S and 188Re. We measured the lethal concentration killing 25% of cells (LC25) with the results of the Tetrazolium dye test. Secondly, we looked for synergy or additivity on cellular toxicity of these two compounds according to cell lines by combined treatment. Synergy or additivity was estimated with the combination index (CI) method (synergy if CI lower than 1, additivity if CI = 1, antagonism if CI upper to 1) based on the Tetrazolium dye tests results. RESULTS Monotherapy dose-dependent toxicities were observed for all three cell lines with 188Re and for the N1S1 and HepG2 cell lines only with S. Combined treatment with 188Re and S showed synergy on HepaRG and N1S1 cell lines and additivity on the HepG2 cell line. CONCLUSIONS The additive, and even synergistic, interest of a combined treatment with 188Re and S is demonstrated in vitro (for the first time to our knowledge) on hepatoma cell lines. This results, in particular for the HepaRG cell line (human HCC), could be explained by the down-regulation of the hepatic drug transporters which are responsible for the Sorafenib efflux in case of simultaneous DNA damages due to a radionuclide exposition. This promising approach now needs to be confirmed in vivo. [Table: see text].

Labeling Techniques with 123 I: Application to Clinical Settings

This chapter deals with the various available labeling techniques using 123 I and the applications of some of the compounds obtained. Many molecules of biological, diagnostic, or pharmaceutical interest are labeled with 123 I to assess metabolism and receptor function. Indeed, this isotope of iodine, routinely available and with suitable nuclear properties allows good imaging with gamma cameras without significantly altering the physico-chemical and biological properties of the original molecule, when carefully labeled. The various iodinating agents employed and labeling techniques with 123 I, from simple isotopic exchange to the use of prosthetic groups, are reviewed here, with emphasis on their respective advantages and disadvantages. 123 I is commercially available and widely used as the most suitable cyclotron-produced radionuclide for SPECT. Four routes of production are used, while about 25 have been suggested and investigated. Many methods of labelling have been described, but only a few allow radiopharmaceutical preparation with good labeling and high specific activity. Furthermore, the relative importance of the various methods varies with time, depending on new synthetic pathways and progress, notably in organometallic chemistry, and no method combines all advantages. During labeling and storage, different factors are responsible for the degradation of radioiodinated tracers, among which are radiolysis and the presence of trace impurities. Iodine loss can occur due to oxygen, light, heat, pH, or solvents.

Labeling Techniques with 123I

This chapter deals with the various available labeling techniques using 123 I and the applications of some of the compounds obtained. Many molecules of biological, diagnostic, or pharmaceutical interest are labeled with 123 I to assess metabolism and receptor function. Indeed, this isotope of iodine, routinely available and with suitable nuclear properties allows good imaging with gamma cameras without significantly altering the physico-chemical and biological properties of the original molecule, when carefully labeled. The various iodinating agents employed and labeling techniques with 123 I, from simple isotopic exchange to the use of prosthetic groups, are reviewed here, with emphasis on their respective advantages and disadvantages. 123 I is commercially available and widely used as the most suitable cyclotron-produced radionuclide for SPECT. Four routes of production are used, while about 25 have been suggested and investigated. Many methods of labelling have been described, but only a few allow radiopharmaceutical preparation with good labeling and high specific activity. Furthermore, the relative importance of the various methods varies with time, depending on new synthetic pathways and progress, notably in organometallic chemistry, and no method combines all advantages. During labeling and storage, different factors are responsible for the degradation of radioiodinated tracers, among which are radiolysis and the presence of trace impurities. Iodine loss can occur due to oxygen, light, heat, pH, or solvents.

Chapter 76 – Labeling Techniques with 123I: Application to Clinical Settings

This chapter deals with the various available labeling techniques using 123 I and the applications of some of the compounds obtained. Many molecules of biological, diagnostic, or pharmaceutical interest are labeled with 123 I to assess metabolism and receptor function. Indeed, this isotope of iodine, routinely available and with suitable nuclear properties allows good imaging with gamma cameras without significantly altering the physico-chemical and biological properties of the original molecule, when carefully labeled. The various iodinating agents employed and labeling techniques with 123 I, from simple isotopic exchange to the use of prosthetic groups, are reviewed here, with emphasis on their respective advantages and disadvantages. 123 I is commercially available and widely used as the most suitable cyclotron-produced radionuclide for SPECT. Four routes of production are used, while about 25 have been suggested and investigated. Many methods of labelling have been described, but only a few allow radiopharmaceutical preparation with good labeling and high specific activity. Furthermore, the relative importance of the various methods varies with time, depending on new synthetic pathways and progress, notably in organometallic chemistry, and no method combines all advantages. During labeling and storage, different factors are responsible for the degradation of radioiodinated tracers, among which are radiolysis and the presence of trace impurities. Iodine loss can occur due to oxygen, light, heat, pH, or solvents.