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. Nuclear Med Rev 2011; 14, 2: 90–9

Radioimmunothérapie vectorisée par des liposomes (étude d'optimisation du ciblage tumoral)

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Etude de la faisabilité de l'immunociblage de liposomes pour la radioimmunothérapie

PARIS-BIUP (751062107) / SudocSudocFranceF

Etude de faisabilité du radiomarquage et du préciblage de liposomes pour la radioimmunothérapie

L'objectif de ce travail est d évaluer l efficacité de liposomes radiomarqués dans l immunociblage des tumeurs. L efficacité de la radioimmunothérapie est en partie limitée par la faible activité que peuvent délivrer les anticorps aux cellules tumorales. Pour résoudre ce problème, nous avons essayé d'encapsuler de la radioactivité dans des liposomes préformés puis de les cibler vers des tumeurs à l aide d anticorps bispécifiques capables de reconnaître à la fois un antigène tumoral et un haptène couplé à la paroi des liposomes. Deux approches ont été testées: le marquage en surface avec de l'indium-111 après couplage à un agent chélatant (DTPA) et le marquage de la phase interne des liposomes à l'aide de composés radio-iodés. Le radiomarquage de la phase aqueuse des liposomes par l intermédiaire d esters activés marqués à l iode confirme que l on peut obtenir des activités spécifiques nettement supérieures à celles décrites dans la littérature. L'originalité de ce travail est le couplage de ces esters à des fonctions amines pré-encapsulées, limitant ainsi la fuite de la radioactivité hors des liposomes. Une étude réalisée chez l'animal a permis d'optimiser la formulation des liposomes, de confirmer la stabilité des radiomarquages et de démontrer la faisabilité d'un ciblage tumoral spécifique chez la souris. Les résultats sont prometteurs et l optimisation du préciblage in vivo des liposomes radiomarqués devrait permettre leur utilisation thérapeutique.The aim of this thesis consists in evaluating efficiency of radiolabeled liposomes for tumors pretargeting. Efficacy of radioimmunotherapy is often limited by the low radioactive doses delivered by the antibody to the tumor cells. One way to solve the problem is the targeting of encapsulated radionuclides. To validate this possibility we have developed methods to radiolabel preformed liposomes properties prior to target them to tumor cells by using bispecific antibodies (anti-antigen and anti-hapten associated to the liposome membrane. Liposomes were then labeled in surface using 111In-DTPA complexe, and internally by active loading of radio-iodinated compounds. The originality of the method consists in encapsulating activated esters that may be readily halogenated, and cross the liposome membrane prior to react with arginine inside the liposomes, increasing the stability of the radiolabeling. Animal studies have been initiated to demonstrate the in vivo stability of the radiolabeling and the capacity of these liposomes to specifically deliver therapeutic doses of radioactivity to tumor cells. Optimization of the pretargeting with this radiolabeled liposomes should permit therapeutic use.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Clinical Advances and Perspectives in Targeted Radionuclide Therapy

Targeted radionuclide therapy has become increasingly prominent as a nuclear medicine subspecialty. For many decades, treatment with radionuclides has been mainly restricted to the use of iodine-131 in thyroid disorders. Currently, radiopharmaceuticals, consisting of a radionuclide coupled to a vector that binds to a desired biological target with high specificity, are being developed. The objective is to be as selective as possible at the tumor level, while limiting the dose received at the healthy tissue level. In recent years, a better understanding of molecular mechanisms of cancer, as well as the appearance of innovative targeting agents (antibodies, peptides, and small molecules) and the availability of new radioisotopes, have enabled considerable advances in the field of vectorized internal radiotherapy with a better therapeutic efficacy, radiation safety and personalized treatments. For instance, targeting the tumor microenvironment, instead of the cancer cells, now appears particularly attractive. Several radiopharmaceuticals for therapeutic targeting have shown clinical value in several types of tumors and have been or will soon be approved and authorized for clinical use. Following their clinical and commercial success, research in that domain is particularly growing, with the clinical pipeline appearing as a promising target. This review aims to provide an overview of current research on targeting radionuclide therapy

DTPA-Coated Liposomes as a New Delivery Vehicle for Plutonium Decorporation

International audienceAdministration of diethylenetriaminepentaacetic acid (DTPA) is the treatment approach used to promote the decorporation of internalized plutonium. Here we evaluated the efficacy of PEGylated liposomes coated with DTPA, primarily designed to prevent enhanced plutonium accumulation in bones, compared to marketed nonliposomal DTPA and liposomes encapsulating DTPA. The comparative effects were examined in terms of reduction of activity in tissues of plutonium-injected rats. The prompt treatment with DTPA-coated liposomes elicited an even greater efficacy than that with liposome-encapsulated DTPA in limiting skeletal plutonium. This advantage, undoubtedly due to the anchorage of DTPA to the outer layer of liposomes, is discussed, as well as the reason for the loss of this superiority at delayed times after contamination. Plutonium complexed with DTPA-coated liposomes in extracellular compartments was partly diverted into the liver and the spleen. These complexes and those directly formed inside hepatic and splenic cells appeared to be degraded, then released from cells at extremely slow rates. This transitory accumulation of activity, which could not be counteracted by combining both liposomal forms, entailed an underestimation of the efficacy of DTPA-coated liposomes on soft tissue plutonium until total elimination probably more than one month after treatment. DTPA-coated liposomes may provide the best delivery vehicle of DTPA for preventing plutonium deposition in tissues, especially in bone where nuclides become nearly impossible to remove once fixed. Additional development efforts are needed to limit the diversion or to accelerate cell release of plutonium bound to DTPA-coated liposomes, using a labile bond for DTPA attachment

Delivery of DTPA through Liposomes as a Good Strategy for Enhancing Plutonium Decorporation Regardless of Treatment Regimen

International audienceIn this study, we assessed the efficacy of unilamellar 110-nm liposomes encapsulating the chelating agent diethylenetriaminepentaacetic acid (DTPA) in plutonium-exposed rats. Rats were contaminated by intravenous administration of the soluble citrate form of plutonium. The comparative effects of liposomal and free DTPA at similar doses were examined in terms of limitation of alpha activity burden in rats receiving various treatment regimens. Liposomal DTPA given at 1 h after contamination more significantly prevented the accumulation of plutonium in tissues than did free DTPA. Also, when compared to free DTPA, liposome-entrapped DTPA was more efficient when given at late times for mobilization of deposited plutonium. In addition, repeated injections of liposomal DTPA further improved the removal of plutonium compared to single injection. Various possible mechanisms of action for DTPA delivered through liposomes are discussed. The advantage of liposomal DTPA over free DTPA was undoubtedly directly and indirectly due to the better cell penetration of DTPA when loaded within liposomes, mainly in the tissues of the mononuclear phagocytic system. The decorporation induced by liposomal DTPA may result first from intracellular chelation of plutonium deposited in soft tissues, predominantly in the liver. Afterwards, the slow release of free DTPA molecules from these same tissues may enable a sustained action of DTPA, probably mainly by extracellular chelation of plutonium available on bone surfaces. In conclusion, decorporation of plutonium can be significantly improved by liposomal encapsulation of DTPA regardless of the treatment regimen applied

Promising Scandium Radionuclides for Nuclear Medicine: A Review on the Production and Chemistry up to In Vivo Proofs of Concept

International audienceScandium radionuclides have been identified in the late 1990s as promising for nuclear medicine applications, but have been set aside for about 20 years. Among the different isotopes of scandium, 43Sc and 44Sc are interesting for positron emission tomography imaging, whereas 47Sc is interesting for therapy. The 44Sc/47Sc or 43Sc/47Sc pairs could be thus envisaged as true theranostic pairs. Another interesting aspect of scandium is that its chemistry is governed by the trivalent ion, Sc3+. When combined with its hardness and its size, it gives this element a lanthanide-like behavior. It is then also possible to use it in a theranostic approach in combination with 177Lu or other lanthanides. This article aims to review the progresses that have been made over the last decade on scandium isotope production and coordination chemistry. It also reviews the radiolabeling aspects and the first (pre) clinical studies performed