MSOR04 Presentation Time: 8:15 AM

Purpose

Diffusing alpha-emitter radiation therapy (Alpha-DaRT) is a brachytherapy modality using implantable seeds impregnated with ∼2µCi of ²²⁴Ra to treat solid tumors. Short-lived alpha-particle emitting atoms are released in the decay chain of ²²⁴Ra. From this decay, ²²⁰Rn and ²¹²Pb atoms are of interest due to their ability to diffuse among the tumor cells undergoing alpha decay and transforming into alpha-emitting daughters. The diffusion will contribute to a high-dose region up to a few mm around the source, overcoming the short-range of alpha-particles in tissue. The diffusion lengths (L_diff) of these alpha-emitting atoms vary across different tumor types, leading to a non-uniform dose distribution. This study investigates the L_diff in an orthotopic intra-rectal animal model designed for colorectal adenocarcinoma.

Materials and Methods

HT-29 colorectal adenocarcinoma cells were injected into the submucosal layer of the intestinal wall of 28 NSG mice. The tumors growth and position were monitored using a 7T MRI scanner, until reaching 5-7 mm in diameter, then separated into control (n=9), inert (n=9) and active groups. The active group was further divided into two, whether Alpha-DaRT source was injected in rectal muscle (n=4) or in the tumor (n=6). The placement of the sources was confirmed by MRI. After four days of exposure, the tumors, and organs at risk (OARs) (ie. kidneys, bladder, and liver) were collected and measured using gamma spectroscopy, measuring the activity from ²¹²Pb. Autoradiographs were acquired from the tumors and OARs histological slides using a Typhoon 9500. Slides were stained with H&E, CD-31 and cleaved-caspase 3 (CC-3) for tissue damage, vascularity, and apoptosis, respectively. The autoradiography responses were fit with a diffusion model and the photostimulated luminescence (PSL) was converted into measured activities. A pathologist measured each groups’ necrotic areas, and the CD-31 and CC-3 tumor sections were scored for positively stained cells between each group.

Results

The initial findings indicate a measured L_diff of 0.23±0.09 mm in muscle tissue versus 0.5-1.0 mm in tumor, reflecting the inter-variability of the tumor microenvironment among mice and the placement of radiation sources (Figure 1A). A ²¹²Pb diffusion leakage probability (²¹²Pb_leakage) was noted due to its ability to bind to proteins and/or red blood cells, leading to the escape of ²¹²Pb from the tumor to the OARs. The ²¹²Pb_leakage measured between 54-93 % for the tumors. A linear relationship between ²¹²Pb_leakage and the activity uptake in the kidneys was observed. The kidneys had the highest activity of the OARs, measuring between 0.255±0.0025 kBq and 0.85±0.0046 kBq. The autoradiographs show a higher activity in the cortex compared to the medulla of the kidneys (Figure 1B). Most tumors had a central necrotic area, with increased vascular regions at the periphery. Additionally, the CD-31 and CC-3-stained samples indicated a lower vascularity score in the active tumor group, suggesting impaired vascularity in the presence of alpha-radiation. The size of the necrotic regions had a statistically significant difference (p=0.034) in the active tumor group. Further experiments are in progress to increase the sample size of the active groups.

Conclusions

The first in-vivo L_diff measurements for the Alpha-DaRT source in an orthotopic intra-rectal animal model for colorectal adenocarcinoma were completed. The observed L_diff aligns with existing literature for healthy muscle tissue, while revealing a substantial L_diff range in rectal tumors. This underscores the importance of tumor specific L_diff for optimal outcome.