PO.ET07.02 · 实验与分子治疗
在等摩尔静脉给药后，Re(CO)3-phenformin与phenformin在小鼠PDAC模型中的药代动力学/药效学相关性及生物分布比较
Pharmacokinetic/pharmacodynamic correlation and biodistribution of Re (CO)3-phenformin compared with phenformin in murine PDAC model following equimolar intravenous dosing
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摘要 Abstract
中文摘要
Re(CO)3-phenformin（Re-phen）是一种新合成的铼双胍复合物，最近被报道并进行了结构表征，作为一种潜在的抗癌剂。然而，其体内药代动力学（PK）、生物分布（BD）、代谢命运和PK/药效学（PK/PD）特性的全面评估尚未得到表征。在本研究中，我们对Re-phen与Phenformin（Phen）进行了整合的PK、BD和PK/PD分析，在携带PDAC的小鼠中连续三次等摩尔静脉给药（每次剂量26.26 μmol/kg），并额外定量Re-phen在体内向Phen的生物转化，以支持母体代谢物暴露建模。使用严格验证的LC-MS/MS检测分析了最后一次给药后采集的血液和主要器官（肿瘤、胰腺、肝、肾、脾、肺）。Re-phen在所有器官中的组织沉积明显高于Phen，包括肿瘤（3.05±1.86 vs 0.05±0.02 nmol/g，**p<0.01）、胰腺（61.64±36.24 vs 0.08±0.05 nmol/g，**p<0.01）、肝（38.27±20.08 vs 0.16±0.06 nmol/g，***p<0.001）、肾（22.27±5.80 vs 0.08±0.03 nmol/g，****p<0.0001）、脾（4.60±1.36 vs 0.29±0.07 nmol/g，****p<0.0001）和肺（4.51±1.40 vs 0.13±0.04 nmol/g，****p<0.0001），显示出广泛的分布和优先的组织滞留。Re-phen还表现出可测量的体内向Phen的转化，代谢分数（Fm）约为11%，AUC比值（Phen/Re-phen）为0.22，表明母体化合物及其转化的Phen均对全身暴露有贡献。3D PK/PD分析显示Re-Phen及其代谢物Phenformin的AUCs与终末肿瘤重量之间存在统计学显著的负相关。相比之下，Phenformin与肿瘤重量仅表现出中等的、无统计学意义的2D相关性（r = -0.800，p = 0.1333），支持Re-Phen更优的抗肿瘤疗效。这些结果表明Re-phen显示出明确的暴露-疗效关系，且全身暴露是其抗肿瘤反应的关键驱动因素。总的来说，本研究提供了首个全面的体内证据，界定了Re-phen的PK、生物分布、代谢转化和PK/PD行为，突显了其优越的肿瘤递送、可测量的母体-代谢物相互作用以及强烈的暴露驱动抗肿瘤效应。这些发现支持进一步开发Re-phen作为一种基于铼的治疗剂，以及作为用于胰腺癌的Re/99mTc-phen诊疗一体化平台的核心组成部分。
查看英文原文 English abstract
Re (CO)3-phenformin (Re-phen) is a newly synthesized rhenium biguanide complex recently reported and structurally characterized as a potential anticancer agent. However, a comprehensive evaluation of its in vivo pharmacokinetics (PK), biodistribution (BD), metabolic fate, and PK/pharmacodynamic (PK/PD) properties has not yet been characterized. In this study, we conducted an integrated PK, BD, and PK/PD analysis of Re-phen compared with Phenformin (Phen) following three consecutive equimolar intravenous doses (26.26 µmol/kg per dose) in PDAC-bearing mice, with additional quantification of in vivo biotransformation of Re-phen to Phen to support parent metabolite exposure modeling. Blood collected after the final dose and major organs (tumor, pancreas, liver, kidney, spleen, lung) were analyzed using a rigorously validated LC-MS/MS assay. Re-phen achieved markedly higher tissue deposition than Phen across all organs, including tumor (3.05 ± 1.86 vs 0.05 ± 0.02 nmol/g, **p<0.01), pancreas (61.64 ± 36.24 vs 0.08 ± 0.05 nmol/g, **p<0.01), liver (38.27 ± 20.08 vs 0.16 ± 0.06 nmol/g, ***p<0.001), kidney (22.27 ± 5.80 vs 0.08 ± 0.03 nmol/g, ****p<0.0001), spleen (4.60 ± 1.36 vs 0.29 ± 0.07 nmol/g, ****p<0.0001), and lung (4.51 ± 1.40 vs 0.13 ± 0.04 nmol/g, ****p<0.0001), demonstrating extensive distribution and preferential tissue retention. Re-phen also exhibited measurable in vivo conversion to Phen, with a fraction metabolized (Fm) of ~11% and an AUC Ratio (Phen/Re-phen) of 0.22, indicating that both the parent compound and its converted Phen contribute to systemic exposure. 3D PK/PD analysis demonstrated a statistically significant inverse correlation between the AUCs of Re-Phen and its metabolite Phenformin and terminal tumor weight. By comparison, Phenformin exhibited only a moderate, non-significant 2D correlation with tumor weight (r = -0.800, p = 0.1333), supporting the superior antitumor efficacy of Re-Phen. These results indicate that Re-phen displayed a clear exposure-efficacy relationship and that systemic exposure is a key driver of its anti-tumor response. Collectively, this study provides the first comprehensive in vivo evidence defining the PK, biodistribution, metabolic conversion, and PK/PD behavior of Re-phen, highlighting its superior tumor delivery, measurable parent-metabolite interplay, and strong exposure-driven antitumor effect. These findings support further development of Re-phen as a rhenium-based therapeutic and as a core component of the Re/99mTc-phen theranostic platform for pancreatic cancer.
利益披露 Disclosure
A. Mohammad Gholizadeh, None..
F. Dagher, None..
M. Skillman, None..
A. Li, None..
D. S. Chow, None.