Ionic liquid supported organotin reagents to prepare molecular imaging and therapy agents.

Efficiency of ionic liquid supported organotin reagents in halodemetalation reaction has been investigated. High radiochemical yields of astatinated and iodinated compounds have been obtained using simple work-up procedure. This methodology represents a straightforward approach for the preparation of molecular imaging and therapy agents in nuclear medicine.

Improvement of the Targeting of Radiolabeled and Functionalized Liposomes with a Two-Step System Using a Bispecific Monoclonal Antibody (Anti-CEA × Anti-DTPA-In).

UNLABELLED: This study proposes liposomes as a new tool for pretargeted radioimmunotherapy (RIT) in solid tumors. Tumor pretargeting is obtained by using a bispecific monoclonal antibody [BsmAb, anti-CEA × anti-DTPA-indium complex (DTPA-In)] and pegylated radioactive liposomes containing a lipid-hapten conjugate (DSPE-PEG-DTPA-In). In this work, the immunospecificity of tumor targeting is demonstrated both in vitro by fluorescence microscopy and in vivo by biodistribution studies. METHODS: Carcinoembryonic antigen (CEA)-expressing cells (LS174T) were used either in cell culture or as xenografts in nude mice. Doubly fluorescent liposomes or doubly radiolabeled liposomes were, respectively, used for in vitro and in vivo studies. In each case, a tracer of the lipid bilayer [rhodamine or indium-111 ((111)In)] and a tracer of the aqueous phase [fluorescein or iodine-125 ((125)I)] were present. The targeting of liposomes was assessed with BsmAb for active targeting or without for passive targeting. RESULTS: Data obtained with the lipid bilayer tracer showed a fluorescent signal on cell membranes two to three times higher for active than for passive targeting. This immunospecificity was confirmed in vivo with tumor uptake of 7.5 ± 2.4% ID/g (percentage of injected dose per gram of tissue) for active targeting versus 4.5 ± 0.45% ID/g for passive targeting (p = 0.03). Regarding the aqueous phase tracer, results are slightly more contrasted. In vitro, the fluorescent tracer seems to be released in the extracellular matrix, which can be correlated with the in vivo data. Indeed, the tumor uptake of (125)I is lower than that of (111)In: 5.1 ± 2.5% ID/g for active targeting and 2.7 ± 0.6% ID/g for passive targeting, but resulted in more favorable tumor/organs ratios. CONCLUSION: This work demonstrated the tumor targeting immunospecificity of DSPE-PEG-DTPA-In liposomes by two different methods. This original and new approach suggests the potential of immunospecific targeting liposomes for the RIT of solid tumors.

Radioiodinated and astatinated NHC rhodium complexes: synthesis.

INTRODUCTION: The clinical development of radioimmunotherapy with astatine-211 is limited by the lack of a stable radiolabeling method for antibody fragments. An astatinated N-heterocyclic carbene (NHC) Rhodium complex was assessed for the improvement of radiolabeling methodologies with astatine. METHODS: Wet harvested astatine-211 in diisopropyl ether was used. Astatine was first reduced with cysteine then was reacted with a chlorinated Rh-NHC precursor to allow the formation of the astatinated analogue. Reaction conditions have been optimized. Astatine and iodine reactivity were also compared. Serum stability of the astatinated complex has been evaluated. RESULTS: Quantitative formation of astatide was observed when cysteine amounts higher than 46.2 nmol/µl of astatine solution were added. Nucleophilic substitution kinetics showed that high radiolabeling yields were obtained within 15 min at 60°C (88%) or within 5 min at 100°C (95%). Chromatographic characteristics of this new astatinated compound have been correlated with the cold iodinated analog ones. The radioiodinated complex was also synthesized from the same precursor (5 min. at 100°C, up to 85%) using [(125)I]NaI as a radiotracer. In vitro stability of the astatinated complex was controlled after 15 h incubation in human serum at 4°C and 37°C. No degradation was observed, indicating the good chemical and enzymatic stability. CONCLUSION: The astatinated complex was obtained in good yield and exhibited good chemical and enzymatic stability. These preliminary results demonstrate the interest of this new radiolabeling methodology, and further functionalizations should open new possibilities in astatine chemistry. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: Although there are many steps and pitfalls before clinical use for a new prosthetic group from the family of NHC complexes, this work may open a new path for astatine-211 targeting.

Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO--a selected review.

During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (=FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical.

Feasibility of the radioastatination of a monoclonal antibody with astatine-211 purified by wet extraction.

Astatine-211, a most promising α-particle emitter for targeted radiotherapy, is generally obtained by high-temperature distillation. However, a liquid-liquid extraction procedure (wet extraction) has also been described. The purpose of this study was to develop and optimize the labelling of the stannylated-activated ester N-hydroxysuccinimidyl-meta-trimethylstannylbenzoate ester (MeSTB) with astatine-211 extracted in di-isopropylether (DIPE) in the presence of the oxidant N-chlorosuccinimide (NCS). The effect of final volume, incubation duration and NCS amounts on radiolabelling yield was studied. The best yields (85-90%) of N-hydroxysuccinimidyl-meta-[(211)At]astatobenzoate ester (SAB) were obtained with 20 nmol of MeSTB, 100 nmol of NCS in 120 µL of DIPE after 15 min. The astatine-211-labelled-activated ester was then used to radiolabel a monoclonal antibody (mAb). The labelling yield was 20-25% and the radiochemical purity was 97-99%. These results show that mAbs may be efficiently labelled with astatine-211 obtained by wet extraction, a fully automatable technique that may prove to be a useful alternative to dry distillation for high activity labelling of radiopharmaceuticals. Copyright © 2008 John Wiley & Sons, Ltd.

Pegylated nanocapsules produced by an organic solvent-free method: Evaluation of their stealth properties.

PURPOSE: To develop from an original process, a novel generation of stealth lipidic nanocapsules in order to improve the lipophilic drug delivery in accessible sites. MATERIALS AND METHODS: Nanocapsules covered by PEG1500 stearate were obtained by a low energy emulsification method. Conductivity measurements and ternary diagram were performed to describe the formulation mechanism. Hemolytic dosage CH50 and pharmacokinetic study in rats have been achieved in order to study the stealth properties of nanocapsules. RESULTS: Transition from an O/W emulsion to a w/O/W emulsion was necessary to produce PEG1500 stearate nanocapsules. Interestingly nanocapsules with a size around 26 nm and a polydispersity index inferior to 0.1 were obtained. The CH50 test has revealed a very weak complement consumption in the presence of such nanocapsules. Moreover, after intravenous injection into rats, PEG1500 stearate nanocapsules exhibited long circulating properties. The experimental data support the concept of steric repulsion of the surface towards proteins, displayed by nanocapsules covered with PEG1500 stearate. These in vivo results were in agreement with the PEG1500 density calculated at the nanocarrier surface. CONCLUSIONS: Injectable drug carriers have been developed. Their long-circulating properties could confer them a strong potential for lipophilic drug targeting.

99mTc/188Re-labelled lipid nanocapsules as promising radiotracers for imaging and therapy: formulation and biodistribution.

PURPOSE: This study focuses on a promising carrier system for imaging and therapeutic purposes using lipid nanocapsules. To assess their potential for clinical use, we labelled nanocapsules with (99m)Tc and (188)Re and analysed some kinetic biodistribution parameters after intravenous injection in rats. METHODS: Lipophilic complexes [(99m)Tc/(188)Re(S(3)CPh)(2)(S(2)CPh)] ((99m)Tc/(188)Re-SSS) were encapsulated within the nanoparticles during their manufacture with quantitative yield and satisfactory radiochemical purity. Rats were injected intravenously with 3.7 MBq (99m)Tc/(188)Re-labelled nanocapsules and sacrificed at 5, 15 and 30 min and 1, 2, 4, 8, 12, 16, 20 and 24 h. RESULTS: Dynamic scintigraphic acquisitions showed predominant hepatic uptake, and ex vivo counting indicated a long circulation time of labelled nanocapsules, with a half-life of 21+/-1 min for (99m)Tc and 22+/-2 min for (188)Re. Very weak urinary elimination was observed, indicating good stability of (99m)Tc and (188)Re labelling. CONCLUSION: (99m)Tc/(188)Re-SSS nanocapsules can be obtained with high yield and satisfactory radiochemical purity. The biodistributions of (99m)Tc/(188)Re-labelled nanocapsules are close to those of classical PEG-coated particles and show good stability of (188)Re/(99m)Tc-SSS labelling.