High resolution digital autoradiographic and dosimetric analysis of heterogeneous radioactivity distribution in xenografted prostate tumors

Purpose: The frst main aim of this study was to illustrate the absorbed dose rate distribution from 177Lu in sections of xenografted prostate cancer (PCa) tumors using high resolution digital autoradiography (DAR) and compare it with hypothetical identical radioactivity distributions of 90Y or 7 MeV alpha-particles. Three dosimetry models based on either dose point kernels or Monte Carlo simulations were used and evaluated. The second and overlapping aim, was to perform DAR imaging and dosimetric analysis of the distribution of radioactivity, and hence the absorbed dose rate, in tumor sections at an early time point after injection during radioimmunotherapy using 177Lu-h11B6, directed against the human kallikrein 2 antigen. Methods: Male immunodefcient BALB/c nude mice, aged 6-8 w, were inoculated by subcutaneous injection of ∼107 LNCaP cells in a 200 μl suspension of a 1:1 mixture of medium and Matrigel. The antibody h11B6 was conjugated with the chelator CHX-A''-DTPA after which conjugated h11B6 was mixed with 177LuCl3. The incubation was performed at room temperature for 2 h, after which the labeling was terminated and the solution was purifed on a NAP-5 column. About 20 MBq 177Lu-h11B6 was injected intravenously in the tail vein. At approximately 10 h postinjection (hpi), the mice were sacrifced and one tumor was collected from each of the fve animals and cryosectioned into 10 μ m thick slices. The tumor slices were measured and imaged using the DAR MicroImager system and the M3Vision software. Then the absorbed dose rate was calculated using a dose point kernel generated with the Monte Carlo code Gate v7.0. Results: The DAR system produced high resolution images of the radioactivity distribution, close to the resolution of single PCa cells. The DAR images revealed a pronounced heterogeneous radioactivity distribution, i.e., count rate per area, in the tumors, indicated by the normalized intensity variations along cross sections as mean ± SD: 0.15±0.15, 0.20±0.18, 0.12±0.17, 0.15±0.16, and 0.23±0.22, for each tumor section, respectively. The absorbed dose rate distribution for 177Lu at the time of dissection 10 hpi showed a maximum value of 2.9±0.4 Gy/h (mean ± SD), compared to 6.0±0.9 and 159±25 Gy/h for the hypothetical 90Y and 7 MeV alpha-particle cases assuming the same count rate densities. Mean absorbed dose rate values were 0.13, 0.53, and 6.43 Gy/h for 177Lu, 90Y, and alpha-particles, respectively. Conclusions: The initial uptake of 177Lu-h11B6 produces a high absorbed dose rate, which is important for a successful therapeutic outcome. The hypothetical 90Y case indicates a less heterogeneous absorbed dose rate distribution and a higher mean absorbed dose rate compared to 177Lu, although with a potentially increased irradiation of surrounding healthy tissue. The hypothetical alpha-particle case indicates the possibility of a higher maximum absorbed dose rate, although with a more heterogeneous absorbed dose rate distribution.