Feasibility of convection-enhanced delivery of unlabeled <sup>225</sup>Ac for glioblastoma: Transport, dosimetry, and clonogenic survival modeling.

Abstract

BackgroundGlioblastoma (GB) is an aggressive primary brain tumor with local recurrence rates exceeding 90% and a five-year survival rate of approximately 5%. Standard treatments such as surgical resection, external beam radiotherapy (EBRT), and chemotherapy often leave residual tumor cells that are resistant to therapy. Local targeted alpha therapy (TAT) with actinium-225 (225Ac) offers high-linear energy transfer (LET) cytotoxicity but is limited by short diffusion range and elevated intratumoral pressure. Convection-enhanced delivery (CED), which applies mild hydraulic pressure to drive bulk flow, may improve radionuclide penetration.PurposeThis study presents a computational model simulating the distribution of unlabeled 225Ac delivered via CED. The full 2 2 5Ac decay chain (parent + daughters) is included in the dosimetric calculations. By characterizing transport dynamics, full decay-chain dose deposition, and resultant clonogenic survival, the model explores both the therapeutic potential and limitations of CED-based alpha therapy.MethodsA Python-based CED model was developed incorporating diffusion (diffusion coefficient = 1.0 × 10-5 cm2/s), bulk flow (velocity in surgical cavity = 7.0 × 10-5 cm/s; velocity in brain tissue = 5.0 × 10-5 cm/s), and radioactive decay in a radially symmetric brain geometry. Time-dependent activity profiles were imported into the Monte Carlo simulation platform TOol for PArticle Simulation (TOPAS) to calculate voxel-level dose distributions. Simulated dose per decay was converted to clinically relevant administered activity (MBq) and integrated over 50 days, adjusted for a relative biological effectiveness (RBE) of 5 (sensitivity range: 3, 7, and 10), and applied via the linear-quadratic model with tumor repopulation parameters (tumor cell doubling time Tp = 14-50 days; repopulation onset Tk = 0-50 days) to a probabilistic GB cell map.ResultsCED achieved therapeutic doses (≥ 2 Gy (RBE)/ MBq) to ∼1.43 cm from injection sites. A five-injection plan delivering a total of 10 MBq reduced the global survival fraction (SF) from 100% (no alpha therapy) to ∼3.4%, with further reductions to ∼2.0% and ∼1.4% at 20 MBq and 30 MBq, respectively. Residual clonogenic tumor cells were mainly located > 2 cm from injection sites. Sensitivity analysis identified injection site placement and total activity as the dominant efficacy factors, whereas varying the RBE had minimal effect. Early tumor repopulation (Tk ≤ 14 days) substantially reduced control in fast-doubling tumors.ConclusionsThis study supports the feasibility of CED of 225Ac for GB, highlighting the need for optimized catheter placement, dosing, and scheduling to address its limited therapeutic radius and tumor repopulation. While results are promising, model assumptions require refinement, and experimental validation is essential to guide clinical translation.