Nicolas Noiret

188Re-loaded lipid nanocapsules as a promising radiopharmaceutical carrier for internal radiotherapy of malignant gliomas

PurposeLipid nanocapsules (LNC) entrapping lipophilic complexes of 188Re (188Re(S3CPh)2(S2CPh) [188Re-SSS]) were investigated as a novel radiopharmaceutical carrier for internal radiation therapy of malignant gliomas. The present study was designed to evaluate the efficacy of intra-cerebral administration of 188Re-SSS LNC by means of convection-enhanced delivery (CED) on a 9L rat brain tumour model.MethodsFemale Fischer rats with 9L glioma were treated with a single injection of 188Re-SSS LNC by CED 6days after cell implantation. Rats were put into random groups according to the dose infused: 12, 10, 8 and 3Gy in comparison with blank LNC, perrhenate solution (4Gy) and non-treated animals. The radionuclide brain retention level was evaluated by measuring 188Re elimination in faeces and urine over 72h after the CED injection. The therapeutic effect of 188Re-SSS LNC was assessed based on animal survival.ResultsCED of 188Re perrhenate solution resulted in rapid drug clearance with a brain T1/2 of 7h. In contrast, when administered in LNC, 188Re tissue retention was greatly prolonged, with only 10% of the injected dose being eliminated at 72h. Rat median survival was significantly improved for the group treated with 8Gy 188Re-SSS LNC compared to the control group and blank LNC-treated animals. The increase in the median survival time was about 80% compared to the control group; 33% of the animals were long-term survivors. The dose of 8Gy proved to be a very effective dose, between toxic (10–12Gy) and ineffective (3–4Gy) doses.ConclusionsThese findings show that CED of 188Re-loaded LNC is a safe and potent anti-tumour system for treating malignant gliomas. Our data are the first to show the in vivo efficacy of 188Re internal radiotherapy for the treatment of brain malignancy.

188Re-SSS lipiodol: radiolabelling and biodistribution following injection into the hepatic artery of rats bearing hepatoma.

BackgroundAlthough intra-arterial radiation therapy with 131I-lipiodol is a useful therapeutic approach to the treatment of hepatocellular carcinoma, various disadvantages limit its use. AimTo describe the development of a method for the labelling of lipiodol with 188Re-SSS (188Re (S2CPh)(S3CPh)2 complex) and to investigate its biodistribution after injection into the hepatic artery of rats with hepatoma. Methods188Re-SSS lipiodol was obtained after dissolving a chelating agent, previously labelled with 188Re, in cold lipiodol. The radiochemical purity (RCP) of labelling was checked immediately. The 188Re-SSS lipiodol was injected into the hepatic artery of nine rats with a Novikoff hepatoma. They were sacrificed 1, 24 and 48 h after injection, and used for ex vivo counting. ResultsLabelling of 188Re-SSS lipiodol was achieved with a yield of 97.3±2.1%. The immediate RCP was 94.1±1.7%. Ex vivo counting confirmed a predominantly hepatic uptake, with a good tumoral retention of 188Re-SSS lipiodol, a weak pulmonary uptake and a very faint digestive uptake. The ‘tumour/non-tumoral liver’ ratio was high at 1, 24 and 48 h after injection (2.9±1.5, 4.1±4.1 and 4.1±0.7, respectively). ConclusionsUsing the method described here, 188Re-SSS lipiodol can be obtained with a very high yield and a satisfactory RCP. The biodistribution in rats with hepatoma indicates a good tumoral retention of 188Re-SSS lipiodol associated with a predominant hepatic uptake, a weak pulmonary uptake and a very faint digestive uptake. This product should be considered for intra-arterial radiation therapy in human hepatoma.

Lipid nanocapsules loaded with rhenium-188 reduce tumor progression in a rat hepatocellular carcinoma model.

Background Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC188Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC188Re-SSS in a chemically induced hepatocellular carcinoma rat model. Methodology/Principal Findings Animals were treated with an injection of LNC188Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and 188Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC188Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC188Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. Conclusions/Significance Overall, these results demonstrate that internal radiation with LNC188Re-SSS is a promising new strategy for hepatocellular carcinoma treatment.

NMR Stereochemical analysis of chiral alkylsulfoxides with α-methoxyaryl acetic acids

Abstract (S)-α-methoxyphenyl and (S)-α-methoxy-2-naphtyl acetic acids (MPA and 2-NMA) were used as NMR chiral shift reagents for the stereochemtical analysis of alkylsulfoxides. It was shown that the use of C 6 D 6 as NMR solvent increased the magnitude of the observed effects for both 1 H- and 13 C-NMR spectra. Moreover, 2-NMA led to a much longer range effect on the chain but lowered the signal spliting of the α-methylene groups.

Novel six-coordinate oxorhenium(V) '3+2' mixed-ligand complexes carrying the SNO/SN donor atom set

Ligand exchange reactions of oxorhenium(V) precursors with bidentate SN and tridentate Schiff bases derived from the condensation of ketones or aldehydes with dithiocarbazic acid methyl ester (H2NNHC(S)SCH3) produce novel ‘3 +2’ mixed-ligand complexes carrying the SNO/SN donor atom set. Thus, reactions of either [NBu4][ReOCl4] or Na[ReO(Gluconate)2] with SNO ligands (H2L n ) or a mixture of bidentate SN (HL m ) and tridentate SNO (H2L n ) in methanol solutions lead, respectively, to the six-coordinated mixed ligand oxorhenium(V) compounds of types [ReO(L n )(HL n )] and [ReO(L n )(L m )], combining one tridentate dianionic S − NO − donor Schiff base (L) and one bidentate anionic S − N donor ligand (HL). Coordination geometry around rhenium is distorted octahedral with the two SN donor atom sets of each ligand defining the equatorial plane, while apical positions are occupied by the oxo group and the oxygen atom of the tridentate SNO ligand (L), as shown by single-crystal X-ray diffraction structure of [ReO(L 1 )(HL 1 )] 1.

Dienophilic activity of vinyldichloroboranes and their use as partners in Diels–Alder—reductive alkylation of azides in a one-pot reaction

Vinyldichloroboranes react with 1,3-dienes and the sequence Diels–Alder cycloaddition–reductive alkylation of benzyl azide leads directly to secondary amines, therefore, showing that vinyldichloroboranes behave as synthetic equivalents of secondary enamines of defined stereochemistry.

Enantiomeric excess determination of some chiral sulfoxides by NMR: use of (S)-Ibuprofen® and (S)-Naproxen® as shift reagents

Abstract The well known drugs (S)-Ibuprofen and (S)-Naproxen were used as NMR shift reagents for the stereochemical analysis of alkylsulfoxides. It was shown that (S)-Naproxen could be worthwhile substituted to (S)-MPA or (S)-2-NMA for the stereochemical analysis of some chiral alkyl sulfoxides.

Development of 99mTc labelled Lipiodol: biodistribution following injection into the hepatic artery of the healthy pig

BackgroundWe develop a method for the radiolabelling of Lipiodol with 99mTc, using a lipophilic complex, [99mTc-(S2CPh)(S3Ph)2], dissolved in Lipiodol (99mTc-SSS Lipiodol). ResultsThe labelling yield is high (96±0.8%), and the radiochemical purity satisfactory (92±2.6%). This labelling is reproducible and stable for up to 24 h in vitro. Studies carried out after injection into the hepatic artery of the healthy pig show that the biodistribution of 99mTc-SSS Lipiodol is comparable with that observed for 188Re Lipiodol. Materials and methodsThe 99mTc-SSS lipiodol was obtained after dissolving a chelating agent, previously labelled with 99mTc, in cold lipiodol. The radiochemical purity (RCP) of the labelling was checked immediately and at 24 h. The 99mTc-SSS lipiodol was injected into the hepatic artery of four healthy pigs for an ex-vivo biodistribution study. An autoradiographic study was performed in two cases. ConclusionsApart from the specific interest of a Lipiodol-bearing technetiated agent for carrying out dosimetric studies, the labelling of Lipiodol with 99mTc is a preliminary step towards the use of radiolabelling with the 188Re analogue.

Rhenium-188 and technetium-99m nitridobis(N-ethoxy-N-ethyldithiocarbamate) leucocyte labelling radiopharmaceuticals: [188ReN(NOET)2] and [99mTcN(NOET)2], NOET = Et(EtO)NCS2: their in vitro localization and chemical behaviour.

In this study, we have investigated the preparation of rhenium-188 nitridobis(N-ethoxy-N-ethyldithiocarbamate) [188ReN(NOET)2] (NOET = Et(EtO)NCS2), analogous to the known technetium-99m radiopharmaceutical. The new 188Re complex was synthesized in good yield with a satisfactory radiochemical purity, using a kit method. The subcellular localization of both radiopharmaceuticals in granulocytes was observed by microautoradiography. The uptake was independent of the radionuclide and predominantly nuclear. Furthermore, HPLC was used to characterize the 99mTc complex before and after blood cell labelling and revealed that the intact radiopharmaceutical was involved.

New bis(dithiocarboxylato)nitridotechnetium-99m radiopharmaceuticals for leucocyte labelling: In vitro and In vivo studies

Dithiocarboxylate ligands were synthesized and characterised. New nitrido 99m-technetium complexes were obtained with these ligands and identified by thin layer chromatography. The nitrido complexes were tested in vitro in whole blood for leucocyte labelling and the design of the ligand was optimized. Best results were obtained with aliphatic linear ligands, containing 9 to 11 atoms of carbon. The in vivo experiment failed because an inflammated area could not be visualized by gamma imaging, the cell labelling mechanism being probably different.