Comparison of S-Values and Absorbed Dose Rates at the Cellular Level in Prostate Cancer Cells Irradiated with ¹⁷⁷Lu and ²²⁵Ac Labelled Compounds

Introduction: Radiopharmaceutical therapies with ¹⁷⁷Lu and ²²⁵Ac labelled pharmaceuticals are increasing in popularity and have shown success in the treatment of malignancies such as prostate and neuroendocrine cancers. However, the dose deposition of ¹⁷⁷Lu and ²²⁵Ac are different at the cellular level due to the differing properties between beta and alpha emissions, such as the particle range, the number of particle interactions, and the energy deposition in their tracks. Internalization properties of the pharmaceutical, i.e. whether the pharmaceutical crosses the membrane into the cytoplasm, may also impact the therapeutic efficacy. This work aims to compare S-values and relative absorbed dose rates to the nucleus, nuclear membrane, cytoplasm, and membrane of a LNCaP prostate cancer cell irradiated with either ¹⁷⁷Lu or ²²⁵Ac. While this work focuses on the macroscopic quantities such as absorbed dose, our long term goal is to incorporate microdosimetry and evaluate the energy deposition on a microscopic level.

Methods: A spherical LNCaP prostate cancer cell was modelled using GATE version 9.0. The cell model includes the nucleus, nuclear membrane, cytoplasm, and membrane which were all water density. The radii of the nucleus and the cytoplasm were based off of the corresponding areas of human LNCaP cells and were 4.48 um and 6.74 um respectively, while each membrane was 5 nm thick. For simulations, the cell was suspended in water and the cytoplasm or membrane was filled with a homogeneous activity distribution of ¹⁷⁷Lu or ²²⁵Ac. Simulations were performed separately for the cytoplasm and membrane. 3D matrices (0.18x0.18x0.18 um) were created containing information about the absorbed dose deposited in each voxel. Separate scoring matrices were created for each cell region and were used to calculate S-values. To determine the relative dose rates of a PSMA targeting compound labelled with ¹⁷⁷Lu and ²²⁵Ac, the ratio of uptake in the cytoplasm and membrane was assessed using a standardized internalization assay in which LNCaP cells were incubated with a ¹⁷⁷Lu labelled PSMA targeting ligand. The activity in each cell region was determined at multiple time points by cleaving the cellular surface proteins using an acid wash and subsequently measuring the activity per region using a gamma counter. The calculated S-values were combined with the cytoplasm to membrane ratio at the 120 minute time point to estimate the relative absorbed dose rates to the cell regions between ¹⁷⁷Lu and ²²⁵Ac.

Results: The calculated S-values are summarized in Table 1. The S-values from the cytoplasm and membrane to the nucleus were 3.03x10^-4 Gy/Bqs and 1.91x10^-4 Gy/Bqs from ¹⁷⁷Lu, and 3.92x10^-2 Gy/Bqs and 2.29x10^-2 Gy/Bqs from ²²⁵Ac, respectively. This corresponds to a 160% and 170% higher dose rate to the nucleus from ¹⁷⁷Lu and ²²⁵Ac respectively when the radiopharmaceutical is internalized into the cell compared to being present only in the membrane. At 120 minutes, the ratio of activity in the membrane to the cytoplasm was 1:2.32. At this time, the relative absorbed dose rates to the nucleus, nuclear membrane, cytoplasm, and cell membrane were 127.3, 121.1, 119.0, and 116.0 times higher with ²²⁵Ac than ¹⁷⁷Lu respectively.

Conclusions: Our model suggests that for a given radioactivity, ²²⁵Ac therapy is 100 times more effective at delivering radiation energy to cancer cells compared to ¹⁷⁷Lu. Futhermore, radiopharmaceuticals which are internalized into the cell may be significantly more effective at cell kill. The next step is to expand our model into the realm of microdosimetry by incorporating lineal energy and specific energy at the cellular or regional levels. We also aim to find correlations between this work and the cell’s biological response to therapy, such as the number of double stranded DNA breaks after incubation with radiolabelled compounds.