Establishing ¹⁷⁷Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer

Abstract

Clinical Lu-PSMA-617 radioligand therapy (RLT) is applied in advanced-stage prostate cancer. However, to the best of our knowledge murine models to study the biologic effects of various activity levels have not been established. The aim of this study was to optimize specific and total activity forLu-PSMA-617 RLT in a syngeneic model of murine prostate cancer. Murine-reconstituted, oncogene-driven prostate cancer cells (0.1 × 10) (RM1), transduced to express human prostate-specific membrane antigen (PSMA), were injected into the left flank of C57Bl6 immunocompetent mice. RLT was performed by administering a single tail vein injection of Lu-PSMA-617 at different formulations for specific (60 MBq at high, 62 MBq/nmol; intermediate, 31 MBq/nmol; or low 15 MBq/nmol specific activity) or total activity (30, 60, or 120 MBq). Organ distribution was determined by ex vivo γ-counter measurement. DNA double-strand breaks were measured using anti-gamma-H2A.X (phospho S139) immunohistochemistry. Efficacy was assessed by serial CT tumor volumetry andF-FDG PET metabolic volume. Toxicity was evaluated 4 wk after the start of RLT. Mean tumor-to-kidney ratios ± SEM were 19 ± 5, 10 ± 5, and 2 ± 0 for high, intermediate, and low (each = 3) specific activity, respectively. Four of 6 (67%) mice treated with intermediate or high specific activity and none of 6 (0%) mice treated with low specific activity or formulation demonstrated significant DNA double-strand breaks (≥5% γ-H2A.X-positive cells). High when compared with intermediate or low specific activity resulted in a lower mean ± SEM tumor load by histopathology (vital tissue, 4 ± 2 vs. 8 ± 3 mm; = 3 vs. 6), day-4F-FDG PET (metabolic volume, 87 ± 23 vs. 118 ± 14 mm; = 6 vs. 12), and day-7 CT (volume, 323 ± 122 vs. 590 ± 46 mm; = 3 vs. 6; = 0.039). Lu-PSMA-617 (120 MBq) with high specific activity induced superior tumor growth inhibition ( = 0.021, = 5/group) without subacute hematologic toxicity ( = 3/group). Lu-PSMA-617 (120 MBq) and high specific activity resulted in the highest efficacy in a syngeneic model of murine prostate cancer. The model will be useful for studying the effects of PSMA-directed RLT combined with potentially synergistic pharmacologic approaches.

Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer

“…Furthermore, uptake of the radioligand may be influenced by target internalization, vascularization, and vascular permeability (10,25). PET signal is influenced by acquisition and reconstruction parameters (26,27).…”

“…RM1 parental cells and RM1 cells stably transduced with human PSMA and SFG-Egfp/Luc (RM1-PGLS; PSMA-positive, green fluorescent protein-positive, and luciferase-positive [PSMA 111 ]) were provided by Dr. Michel Sadelain (Memorial Sloan-Kettering Cancer Center). Generation of the RM1-yellow fluorescent protein subline (RM1-YFP; YFP only, no PSMA transgene insert [PSMA 2 ]), the RM1-low subline (PSMA 1 ), and the RM1-medium subline (PSMA 11 ) was previously described (10).…”

“…68 Ga-PSMA11 (5 mg of precursor) was obtained from the UCLA Biomedical Cyclotron Facility (10). PET/CT was performed on days 7 (all mice) and 8 (RM1-low and RM1-PGLS mice) after tumor induction ( Fig.…”

Radioiodinated progesterone derivative for progesterone receptor targeting with enhanced nucleus uptake via phenylboronic acid conjugation

“…The specificity of 131 I‐EIPBA for PR was tested following the literature method . MCF‐7 cells seeded in 24‐well plates (2 × 10 5 cells per well) were incubated for 24 hours, then washed twice with 1 mL PBS (pH = 7.4) and incubated with or without PR inhibitor (10 μL per well, 1 mg/mL) for 1 hour.…”

“…For the internalization, MCF‐7 cells seeded in 24‐well plates (2 × 10 5 cells per well) were incubated for 24 hours. Wash the cells once with binding buffer; then 450 μL binding buffer was added to each well.…”