Impact of radiopharmaceutical therapy (¹⁷⁷Lu, ²²⁵Ac) microdistribution in a cancer-associated fibroblasts model

Background: The aim of this study is to elucidate the difference in absorbed dose (D_abs) patterns in radiopharmaceutical therapies between alpha emitters (²²⁵Ac) and beta emitters (¹⁷⁷Lu) when targeting cancer-associated fibroblasts (CAF) or tumor cells. Five spherical models with 3 mm diameter were created, representing spherical tumor masses that contain tumor clusters, interspersed with CAFs. The mean distance from a tumor cell to the nearest CAF (L_mean) varied throughout these models from 92 to 1030 µm. D_abs calculations were performed while selecting either CAFs or tumor cells as sources, with Convolution/Superposition with ¹⁷⁷Lu and Monte Carlo simulations (GATE) with ²²⁵Ac. Analyses were conducted with Dose Volume Histograms and efficacy ratios (ER), which represents the ratio of mean D_abs that is deposited in the target volume.

Results: ²²⁵Ac is the most optimal radionuclide when CAFs are both targeted and irradiating themselves, as ERs increase from 1.5 to 3.7 when L_mean increases from 92 to 1030 µm. With ¹⁷⁷Lu, these numbers vary from 1.2 to 2.7. Conversely, when CAFs are sources and tumors are targets with ²²⁵Ac, ERs decreased from 0.8 to 0.1 when L_mean increases from 92 to 1030 µm. With ¹⁷⁷Lu, these numbers vary from 0.9 to 0.3 CONCLUSION: When targeting CAFs to irradiate tumors, the efficacy of using ²²⁵Ac decreases as the average size of the tumor clusters (or L_mean) increases. In such situations, ¹⁷⁷Lu will be more effective than ²²⁵Ac when targeting CAFs due to the longer beta particle range.