Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Nucl Med Biol. 2023 Jul-Aug;122-123:108368. doi: 10.1016/j.nucmedbio.2023.108368. Epub 2023 Jul 19.
Advanced ovarian cancer currently has few therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors bind to nuclear PARP and trap the protein-inhibitor complex to DNA. This work investigates a theranostic PARP inhibitor for targeted radiopharmaceutical therapy of ovarian cancer in vitro and PET imaging of healthy mice in vivo.
[Br]RD1 was synthesized and assessed for pharmacokinetics and cytotoxicity in human and murine ovarian cancer cell lines. [Br]RD1 biodistribution and organ uptake in healthy mice were quantified through longitudinal PET/CT imaging and ex vivo radioactivity measurements. Organ-level dosimetry following [Br]RD1 administration was calculated using RAPID, an in-house platform for absorbed dose in mice, and OLINDA for equivalent and effective dose in human.
The maximum specific binding (B), equilibrium dissociation constant (K), and nonspecific binding slope (NS) were calculated for each cell line. These values were used to calculate the cell specific activity uptake for cell viability studies. The half maximal effective concentration (EC) was measured as 0.17 (95 % CI: 0.13-0.24) nM and 0.46 (0.13-0.24) nM for PARP(+) and PARP(-) expressing cell lines, respectively. The EC was 0.27 (0.21-0.36) nM and 0.30 (0.22-0.41) nM for BRCA1(-) and BRCA1(+) expressing cell lines, respectively. When measuring the EC as a function of cellular activity uptake and nuclear dose, the EC ranges from 0.020 to 0.039 Bq/cell and 3.3-9.2 Gy, respectively. Excretion through the hepatobiliary and renal pathways were observed in mice, with liver uptake of 2.3 ± 0.4 %ID/g after 48 h, contributing to estimated absorbed dose values in mice of 19.3 ± 0.3 mGy/MBq and 290 ± 10 mGy/MBq for [Br]RD1 and [Br]RD1, respectively.
[Br]RD1 cytotoxicity was dependent on PARP expression and independent of BRCA1 status. The in vitro results suggest that [Br]RD1 cytotoxicity is driven by the targeted Meitner-Auger electron (MAe) radiotherapeutic effect of the agent. Further studies investigating the theranostic potential, organ dose, and tumor uptake of [Br]RD1 are warranted.
目前晚期卵巢癌治疗选择有限。多聚（ADP-核糖）聚合酶（PARP）抑制剂与核 PARP 结合并将蛋白-抑制剂复合物捕获到 DNA 上。本研究旨在探讨一种治疗 PARP 的放射性诊断试剂，用于体外卵巢癌靶向放射药物治疗和健康小鼠体内的 PET 成像。
合成 [Br]RD1 并评估其在人源和鼠源卵巢癌细胞系中的药代动力学和细胞毒性。通过纵向 PET/CT 成像和离体放射性测量定量研究 [Br]RD1 在健康小鼠体内的生物分布和器官摄取。使用 RAPID（一种用于小鼠吸收剂量的内部平台）和 OLINDA（用于人类等效和有效剂量）计算 [Br]RD1 给药后的器官水平剂量。
为每个细胞系计算了最大特异性结合（B）、平衡解离常数（K）和非特异性结合斜率（NS）。这些值用于计算细胞活力研究中的细胞特异性活性摄取。PARP（+）和 PARP（-）表达细胞系的半最大有效浓度（EC）分别为 0.17（95%CI：0.13-0.24）nM 和 0.46（0.13-0.24）nM。BRCA1（-）和 BRCA1（+）表达细胞系的 EC 分别为 0.27（0.21-0.36）nM 和 0.30（0.22-0.41）nM。当将 EC 作为细胞活性摄取和核剂量的函数进行测量时，EC 范围为 0.020 至 0.039 Bq/细胞和 3.3 至 9.2 Gy。在小鼠中观察到通过肝胆和肾脏途径排泄，48 小时后肝脏摄取 2.3±0.4 %ID/g，导致 [Br]RD1 和 [Br]RD1 的估计吸收剂量值分别为 19.3±0.3 mGy/MBq 和 290±10 mGy/MBq。
[Br]RD1 的细胞毒性取决于 PARP 表达，与 BRCA1 状态无关。体外结果表明，[Br]RD1 的细胞毒性是由该药物的靶向迈特纳-俄歇电子（MAe）放射治疗效应驱动的。进一步研究 [Br]RD1 的治疗潜力、器官剂量和肿瘤摄取是必要的。
