Objectives Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of 111In-DTPA-5A10, which targets free Prostate Specific Antigen (fPSA), in two animal models. Methods In vivo bio-distribution studies of 111In-DTPA-5A10 were performed in immunodeficient BALB/c-nu or NMRI-nu mice with subcutaneous (s.c.) LNCaP tumors. Targeting-specificity of the tracer was assessed by quantifying the uptake in (a) mice with s.c. xenografts of PSA-negative DU145 cells as well as (b) BALB/c-nu or NMRI-nu mice co-injected with an excess of non-labeled 5A10. Finally, the effect of neonatal Fc-receptor (FcRn) inhibition on the bio-distribution of the conjugate was studied by saturating FcRn-binding capacity with nonspecific IgG1. Results The inherent biological attributes of the mouse model substantially influenced the bio-distribution and pharmacokinetics of 111In-DTPA-5A10. With LNCaP xenografts in BALB/c-nu mice (with intact B and NK cells but with deficient T cells) versus NMRI-nu mice (with intact B cells, increased NK cells and absent T cells), we observed a significantly higher hepatic accumulation (26±3.9 versus 3.5±0.4 %IA/g respectively), and concomitantly lower tumor uptake (25±11 versus 52±10 %IA/g respectively) in BALB/c-nu mice. Inhibiting FcRn by administration of nonspecific IgG1 just prior to 111In-DTPA-5A10 did not change tumor accumulation significantly. Conclusions We demonstrated that the choice of immunodeficient mouse model importantly influence the bio-distribution of 111In-DTPA-5A10. This study further highlighted important considerations in the evaluation of preclinical tracers, with respect to gaining information on their performance in the translational setting. Investigators utilizing xenograft models need to assess not only radiolabeling strategies, but also the host immunological status.
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.
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