In vitro effects and microdosimetry of Astatine-211 for tumor therapy

The aim of this study was to perform various astatine-211 (alpha-particle emitter; T1/2: 7.2 h) and photon irradiation experiments on tumour cells for the evaluation of 211At-radioimmunotherapy, and to find suitable microdosimetric techniques for this purpose.Methods. The in vitro effects of 211At on two human cancer cell lines (Colo-205 and NIH:OVCAR-3) were investigated. Irradiation was performed on low-concentration (10,000 cells/ml) cell suspensions in custom-built rotating phantoms. Centrifuge tube filters were used to determine the cellular uptake of 211At in various forms. Growth assays using 96-well plates were used to determine cell growth kinetics and cell survival. A Monte Carlo computer program was developed to simulate the energy imparted and track length distributions for cell nuclei hit by alpha-particles from different spatial distributions of 211At and the daughter 211Po decays. Four different dosimetric quantities (mean absorbed dose, D; specific energy, z; track length, c; and number of hits, n) were evaluated for use in 211At-radioimmunotherapy.Results. RBEs of 12 ± 2 (Colo-205) and 5.3 ± 0.7 (NIH:OVCAR-3) were found to result from 211At-albumin irradiation. The free 211At concentration in the cell fraction was 174 ± 28 times higher than in the surrounding medium. For 211At-MAb, the cell fraction concentration was 8,000-30,000 times higher than in the medium. An average 31 ± 8 (free 211At) and 26 ± 7 (211At-MAb) decays per cell were required for 37% survival of Colo-205 cells. An average 19 ± 5 decays (free 211At) were required per NIH:OVCAR-3 cell. The best correlation between calculated radiosensitivity from two distributions of 211At decays was seen when the location of the 211Po decays was removed from the original position of the mother 211At decay. Cell surface-bound 211At-MAb yielded similar values of radiosensitivity (D37=0.27 ± 0.08 Gy, z37=0.19 ± 0.06 Gy) to those for non-bound 211At-albumin (D37=0.30 ± 0.08 Gy, z37=0.17 ± 0.05 Gy) when an energy-imparted-based quantity was used. The values of the other quantities did not show such good correlation (c37=7.2 ± 2.0 mm, n37=1.1 ± 0.3 for non-bound and c37=11 ± 3 mm, n37=1.6 ± 0.5 for bound 211At-MAb decays). When the 211Po decays were located at the position of their mother 211At decays, the values for bound decays were D37=0.59 ± 0.17 Gy, z37=0.52 ± 0.15 Gy, c37=32 ± 9 mm, and n37=4.6 ± 1.3. For free 211At irradiation, the best correlation was seen for the assumption that astatine is bound to the cell surface and the 211Po atom is released from the bond (D37=0.46 ± 0.13 Gy, z37=0.37 ± 0.10 Gy, c37=19 ± 5 mm, n37=2.8 ± 0.8).Conclusions. Of 4 microdosimetric quantities, those based on the energy imparted to the cell nuclei provided the most agreement with the data for various types of 211At irradiation. The two associated alpha-particles should be assigned spatially separated origin