Abstract:An alpha--particle irradiator, enabling high--precision irradiation of cells for in--vitro studies, has been constructed. The irradiation source was a 241 Am source, on which well inserts containing cancer cells growing in monolayer were placed. The total radioactivity, uniformity, and alpha--particle spectrum were determined by use of HPGe--detector, Gafchromic™--dosimetry film, and PIPS®--detector measurements, respectively. Monte Carlo simulations were used for dosimetry. Three prostate cancer (LNCaP, DU145… Show more
“…The main alpha emissions from 241 Am at 5.486 MeV (yield 84.5%) and 5.443 (yield 13.0%) are partly energy-degraded in the source volume before exiting through the source window. These results agree with previously published data [ 26 ]. Fig.…”
Section: Resultssupporting
confidence: 94%
“…The source is sealed in an aluminum cover, and the circular active source window is 11.8 mm in diameter and covered by a 0.5 µm palladium coating. The activity was previously estimated to 405 ± 10 kBq [ 26 ].…”
Background
The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets. Since a large variance is expected of alpha particle hits in individual cell nuclei irradiated by an uncollimated alpha-emitting source, the damage induced should have a similar distribution. The induction of DSB can be measured by immunofluorescent γ-H2AX staining. The cell γ-H2AX foci distribution and alpha particle hits distribution should be comparable and thereby verify the necessity to consider the relevant dosimetric volumes.
Methods
A Monte Carlo simulation model of an 241Am source alpha particle irradiation setup was combined with two versions of realistic cell nuclei phantoms. These were generated from DAPI-stained PC3 cells imaged with fluorescent microscopy, one consisting of elliptical cylinders and the other of segmented mesh volumes. PC3 cells were irradiated with the 241Am source for 4, 8 and 12 min, and after 30 min fixated and stained with immunofluorescent γ-H2AX marker. The detected radiation-induced foci (RIF) were compared to simulated RIF.
Results
The mesh volume phantom detected a higher mean of alpha particle hits and energy imparted (MeV) per cell nuclei than the elliptical cylinder phantom, but the mean specific energy (Gy) was very similar. The mesh volume phantom detected a slightly larger variance between individual cells, stemming from the more extreme and less continuous distribution of cell nuclei sizes represented in this phantom. The simulated RIF distribution from both phantoms was in good agreement with the detected RIF, although the detected distribution had a zero-inflated shape not seen in the simulated distributions. An estimate of undetected foci was used to correct the detected RIF distribution and improved the agreement with the simulations.
Conclusion
Two methods to generate cell nuclei phantoms for Monte Carlo dosimetry simulations were tested and generated similar results. The simulated and detected RIF distributions from alpha particle-irradiated PC3 cells were in good agreement, proposing the necessity to consider microscopic targets in alpha particle dosimetry.
“…The main alpha emissions from 241 Am at 5.486 MeV (yield 84.5%) and 5.443 (yield 13.0%) are partly energy-degraded in the source volume before exiting through the source window. These results agree with previously published data [ 26 ]. Fig.…”
Section: Resultssupporting
confidence: 94%
“…The source is sealed in an aluminum cover, and the circular active source window is 11.8 mm in diameter and covered by a 0.5 µm palladium coating. The activity was previously estimated to 405 ± 10 kBq [ 26 ].…”
Background
The development of new targeted alpha therapies motivates improving alpha particle dosimetry. For alpha particles, microscopic targets must be considered to estimate dosimetric quantities that can predict the biological response. As double-strand breaks (DSB) on DNA are the main cause of cell death by ionizing radiation, cell nuclei are relevant volumes necessary to consider as targets. Since a large variance is expected of alpha particle hits in individual cell nuclei irradiated by an uncollimated alpha-emitting source, the damage induced should have a similar distribution. The induction of DSB can be measured by immunofluorescent γ-H2AX staining. The cell γ-H2AX foci distribution and alpha particle hits distribution should be comparable and thereby verify the necessity to consider the relevant dosimetric volumes.
Methods
A Monte Carlo simulation model of an 241Am source alpha particle irradiation setup was combined with two versions of realistic cell nuclei phantoms. These were generated from DAPI-stained PC3 cells imaged with fluorescent microscopy, one consisting of elliptical cylinders and the other of segmented mesh volumes. PC3 cells were irradiated with the 241Am source for 4, 8 and 12 min, and after 30 min fixated and stained with immunofluorescent γ-H2AX marker. The detected radiation-induced foci (RIF) were compared to simulated RIF.
Results
The mesh volume phantom detected a higher mean of alpha particle hits and energy imparted (MeV) per cell nuclei than the elliptical cylinder phantom, but the mean specific energy (Gy) was very similar. The mesh volume phantom detected a slightly larger variance between individual cells, stemming from the more extreme and less continuous distribution of cell nuclei sizes represented in this phantom. The simulated RIF distribution from both phantoms was in good agreement with the detected RIF, although the detected distribution had a zero-inflated shape not seen in the simulated distributions. An estimate of undetected foci was used to correct the detected RIF distribution and improved the agreement with the simulations.
Conclusion
Two methods to generate cell nuclei phantoms for Monte Carlo dosimetry simulations were tested and generated similar results. The simulated and detected RIF distributions from alpha particle-irradiated PC3 cells were in good agreement, proposing the necessity to consider microscopic targets in alpha particle dosimetry.
“…The results show that it is possible to produce detailed knowledge about the radioactivity distribution, close to the resolution of individual PCa cells (i.e., ∼20 µm), 60,61 using the MicroImager and M3Vision software (Fig. 1).…”
The initial uptake of Lu-h11B6 produces a high absorbed dose rate, which is important for a successful therapeutic outcome. The hypotheticalY case indicates a less heterogeneous absorbed dose rate distribution and a higher mean absorbed dose rate compared to Lu, 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.
“…Here, the radiosensitivity parameter of cells to α-particles (ߙ ଵ ) was found to be 1.82 Gy -1 . 27 As cell death results mainly from single alpha-particle interaction events, the relationship between the surviving fraction (SF) and the cell absorbed dose (D) is approximate to a log-linear model. 12 Thus, the survival fraction curve, which resulted from clonogenic assays using an external α-source, followed the linear equation parameters:…”
Section: Radiation Effects In the Tumour Volumementioning
Despite the reported effectiveness of 223 RaCl 2 for treatment of bone metastases, many questions remain regarding its dosimetry and pharmacodynamics. This study models three different 223 RaCl 2 uptake scenarios, comparing their predictions of time to first symptomatic skeletal event to published clinical data. Our results suggest that approaches which assume a uniform biodistribution of 223 Ra throughout metastatic sites do not accurately predict biological effects of α-radionuclide therapies, with exposure of small sub-populations providing superior agreement with clinical data.
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