astatine and Lymphoma--Non-Hodgkin

Alpha-emitting radionuclides exhibit a potential advantage for cancer treatments because they release large amounts of ionizing energy over a few cell diameters (50-80 μm), causing localized, irreparable double-strand DNA breaks that lead to cell death. Radioimmunotherapy (RIT) approaches using monoclonal antibodies labeled with α emitters may thus inactivate targeted cells with minimal radiation damage to surrounding tissues. Tools are needed to visualize and quantify the radioactivity distribution and absorbed doses to targeted and nontargeted cells for accurate dosimetry of all treatment regimens utilizing α particles, including RIT and others (e.g., Ra-223), especially for organs and tumors with heterogeneous radionuclide distributions. The aim of this study was to evaluate and characterize a novel single-particle digital autoradiography imager, the ionizing-radiation quantum imaging detector (iQID) camera, for use in α-RIT experiments.. The iQID camera is a scintillator-based radiation detection system that images and identifies charged-particle and gamma-ray/x-ray emissions spatially and temporally on an event-by-event basis. It employs CCD-CMOS cameras and high-performance computing hardware for real-time imaging and activity quantification of tissue sections, approaching cellular resolutions. In this work, the authors evaluated its characteristics for α-particle imaging, including measurements of intrinsic detector spatial resolutions and background count rates at various detector configurations and quantification of activity distributions. The technique was assessed for quantitative imaging of astatine-211 ((211)At) activity distributions in cryosections of murine and canine tissue samples.. The highest spatial resolution was measured at ∼20 μm full width at half maximum and the α-particle background was measured at a rate as low as (2.6 ± 0.5) × 10(-4) cpm/cm(2) (40 mm diameter detector area). Simultaneous imaging of multiple tissue sections was performed using a large-area iQID configuration (ø 11.5 cm). Estimation of the (211)At activity distribution was demonstrated at mBq/μg-levels.. Single-particle digital autoradiography of α emitters has advantages over traditional film-based autoradiographic techniques that use phosphor screens, in terms of spatial resolution, sensitivity, and activity quantification capability. The system features and characterization results presented in this study show that the iQID is a promising technology for microdosimetry, because it provides necessary information for interpreting alpha-RIT outcomes and for predicting the therapeutic efficacy of cell-targeted approaches using α emitters.

Topics: Animals; Antigens, CD20; Astatine; Autoradiography; Dogs; Equipment Design; Female; Gamma Cameras; Leukocyte Common Antigens; Lymph Nodes; Lymphoma, Non-Hodgkin; Mice; Mice, Nude; Neoplasm Transplantation; Phantoms, Imaging; Radiography; Radioimmunotherapy; Software

The alpha-emitting radionuclide 211At conjugated to the CD20 targeting chimeric monoclonal antibody rituximab was studied to: (a) Estimate radiation dose components to lymphoma and bone marrow (BM) cells exposed in vitro. (b) Calculate the mean absorbed radiation doses in various normal tissues of mice following intravenous injection.. B-lymphoma cells (RAEL) and normal human BM cells were incubated with increasing concentrations of the radioimmunoconjugate. Based on binding kinetics and on measured cellular and nuclear diameters, the radiation doses were calculated using microdosimetric methods.. Targeting of 211At-rituximab to RAEL cells was extensive and stable compared with the binding to BM cells. The absorbed radiation doses from cell-bound activity at an initial activity concentration of 10 kBq ml(-1) were 0.645 and 0.021 Gy to RAEL and BM cells, respectively. In comparison, the contribution from unbound conjugate in the medium during 1h exposure was 0.042 and 0.043 Gy. The D(0) value for RAEL cells was 0.55 Gy, but only 0.34 Gy for BM cells, whereas corresponding D(0) values were 0.72 and 1.21 Gy after a single exposure to external 60Co gamma-rays. Mean absorbed doses of 1.31, 0.48 and 0.36 Gy for blood, lungs and heart were calculated in mice injected with 5.4kBq g(-1) of 211At-rituximab.. Despite the higher inherent sensitivity of the BM cells to the alpha-irradiation, there was, related to the radioactivity concentrations of 211At-rituximab, several logs greater cell kill in RAEL cells, illustrating the tumour-specific nature of the targeting.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antigens, CD20; Astatine; Bone Marrow Cells; Cell Nucleus; Cell Separation; Cells, Cultured; Dose-Response Relationship, Radiation; Flow Cytometry; Gamma Rays; Humans; Isotopes; Kinetics; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred BALB C; Models, Statistical; Protein Binding; Radioimmunoassay; Radiometry; Rituximab; Time Factors; Tumor Cells, Cultured

The ability of an alpha-emitter conjugated to a chimaeric anti-CD20 monoclonal antibody to kill selectively human B-lymphoma cells in vitro is reported. Two B-lymphoma cell lines RAEL and K422, and normal haematopoietic progenitor cells from human bone marrow aspirates were incubated with(211)At-rituximab (Rituxan(R) or MabTheratrade mark) and plated in clonogenic assays for survival analyses. Following 1 h incubation with(211)At-rituximab, in concentrations which gave an initial activity of 50 kBq ml(-1), a high tumour cell to normal bone marrow cell toxicity ratio was obtained; 4.1 to 1.0 log cell kill. Biodistribution studies of(211)At-rituximab in Balb/c mice showed similar stability as that of the iodinated analogue. The data indicate that testing of(211)At-rituximab in human patients is warranted.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Astatine; Cell Death; Cell Survival; Hematopoietic Stem Cells; Humans; Immunoconjugates; Lymphoma, Non-Hodgkin; Radioisotopes; Rituximab; Tumor Cells, Cultured