Characterization of At- species in simple and biological media by high performance anion exchange chromatography coupled to gamma detector.

Astatine is a rare radioelement belonging to the halogen group. Considering the trace amounts of astatine produced in cyclotrons, its chemistry cannot be evaluated by spectroscopic tools. Analytical tools, provided that they are coupled with a radioactive detection system, may be an alternative way to study its chemistry. In this research work, High Performance Anion Exchange Chromatography (HPAEC) coupled to a gamma detector (γ) was used to evaluate astatine species under reducing conditions. Also, to strengthen the reliability of the experiments, a quantitative analysis using a reactive transport model has been done. The results confirm the existence of one species bearing one negative charge in the pH range 27.5. With respect to the other halogens, its behavior indicates the existence of negative ion, astatide At-. The methodology was successfully applied to the speciation of the astatine in human serum. Under fixed experimental conditions (pH 7.47.5 and redox potential of 250 mV) astatine exists mainly as astatide At- and does not interact with the major serum components. Also, the method might be useful for the in vitro stability assessment of 211At-labelled molecules potentially applicable in nuclear medicine

Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors

International audienceBackgroundOverexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line.MethodThe immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated.Results 125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment.ConclusionThese results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging

Interest of Pet Imaging in Multiple Myeloma

The interest of 18Fluoro-deoxyglucose (FDG) positron emission tomography (PET) imaging in the management of patients with multiple myeloma (MM) for the workup at diagnosis and for therapeutic evaluation has recently been demonstrated. FDG-PET is a powerful imaging tool for bone lesions detection at initial diagnosis with high sensitivity and specificity values. The independent pejorative prognostic value on progression-free survival (PFS) and overall survival (OS) of baseline PET-derived parameters (presence of extra-medullary disease (EMD), number of focal bone lesions (FLs), and maximum standardized uptake values [SUVmax]) has been reported in several large independent prospective studies. During therapeutic evaluation, FDG-PET is considered as the reference imaging technique, because it can be performed much earlier than MRI which lacks specificity. Persistence of significant FDG uptake after treatment, notably before maintenance therapy, is an independent pejorative prognostic factor, especially for patients with a complete biological response. So FDG-PET and medullary flow cytometry are complementary tools for detection of minimal residual disease before maintenance therapy. However, the definition of PET metabolic complete response should be standardized. In patients with smoldering multiple myeloma, the presence of at least one hyper-metabolic lytic lesions on FDG-PET may be considered as a criterion for initiating therapy. FDG-PET is also indicated for initial staging of a solitary plasmacytoma so as to not disregard other bone or extra-medullary localizations. Development of nuclear medicine offer new perspectives for MM imaging. Recent PET tracers are willing to overcome limitations of FDG. (11)C-Methionine, which uptake reflects the increased protein synthesis of malignant cells seems to correlate well with bone marrow infiltration. Lipid tracers, such as Choline or acetate, and some peptide tracers, such as (68) Ga-Pentixafor, that targets CXCR4 (chemokine receptor-4, which is often expressed with high density by myeloma cells), are other promising PET ligands. 18F-fludarabine and immuno-PET targeting CD138 and CD38 also showed promising results in preclinical models

Innovative radiopharmaceuticals in oncology and neurology

The aim of this Research Topic was to assemble a series of articles describing basic, preclinical and clinical research studies on radiopharmaceuticals and nuclear medicine. The articles were written by attendees of the third Nuclear Technologies for Health Symposium (NTHS, 10th-11th March 2015, Nantes, Frances) under the auspices of the IRON LabEx (Innovative Radiopharmaceuticals for Oncology and Neurology Laboratory of Excellence). This French network, gathering approximately 160 scientists from 12 academic research teams (Funded by “investissements d’Avenir”), fosters transdisciplinary projects between teams with expertise in chemistry, radiochemistry, radiopharmacy, formulation, biology, nuclear medicine and medical physics. The 12 articles within this resulting eBook present a series of comprehensive reviews and original research papers on multimodality imaging and targeted radionuclide therapy; illustrating the different facets of studies currently conducted in these domains

ImmunoPET to help stratify patients for targeted therapies and to improve drug development

International audienceno abstrac

Alphatherapy, the new impetus to targeted radionuclide therapy?

International audienceno abstrac

Cytotoxic effect of hyperthermia and chemotherapy with platinum salt on ovarian cancer cells: results of an in vitro study.

International audiencePURPOSE: Hyperthermic intraperitoneal chemotherapy is continuously under evaluation in ovarian cancer. The purpose of the present study was to evaluate the effect of chemotherapy, drug concentration and temperature. MATERIALS AND METHODS: A human ovarian carcinoma cell line was used. The effect of hyperthermia combined with chemotherapy was analyzed. RESULTS: When hyperthermia was combined with chemotherapy, the 50% lethal dose (LD(50)) decreased with the duration of exposure. The effect of temperature was similar between 39 and 43 °C for a 30-min exposure. For a 60- to 90-min exposure, the LD(50) was equivalent between 38 and 43 °C. Beyond 40 °C, an increase in platinum salt concentration was necessary to obtain similar results according to the duration of exposure. CONCLUSIONS: The cytotoxic effect of the combination seemed to be potentiated and limited at 40 °C

Biochemical and Immunological Characterization of Nitrate Reductase Deficient nia Mutants of Nicotiana plumbaginifolia

Sixty-five Nicotiana plumbaginifolia mutants affected in the nitrate reductase structural gene (nia mutants) have been analyzed and classified. The properties evaluated were: (a) enzyme-linked immunosorbent assay (two-site ELISA) using a monoclonal antibody as coating reagent and (b) presence of partial catalytic activities, namely nitrate reduction with artificial electron donors (reduced methyl viologen, reduced flavin mononucleotide, or reduced bromphenol blue), and cytochrome c (Cyt c) reduction with NADH. Four classes have been defined: 40 mutants fall within class 1 which includes all mutants that have no protein detectable in ELISA and no partial activities; mutants of classes 2 and 3 exhibit an ELISA-detectable nitrate reductase protein and lack either Cyt c reductase activity (class 2: fourteen mutants) or the terminal nitrate reductase activities (class 3: eight mutants) of the enzyme. Three mutants (class 4) are negative in the ELISA test, lack Cyt c reductase activity, and lack or have a very low level of reduced methyl viologen or reduced flavin mononucleotide-nitrate reductase activities; however, they retain the reduced bromphenol blue nitrate reductase activity. Variations in the degrees of terminal nitrate reductase activities among the mutants indicated that the flavin mononucleotide and methyl viologen-dependent activities were linked while the bromphenol blue-dependent activity was independent of the other two. The putative positions of the lesions in the mutant proteins and the nature of structural domains of nitrate reductase involved in each partial activity are discussed