Targeted α particle therapy (TAT) is ideal for treating disease while minimizing damage to surrounding nontargeted tissues due to short path length and high linear energy transfer (LET). We developed a TAT for metastatic uveal melanoma, targeting the melanocortin-1 receptor (MC1R), which is expressed in 94% of uveal melanomas. Two versions of the therapy are being investigated: ²²⁵Ac-DOTA-Ahx-MC1RL (²²⁵Ac-Ahx) and ²²⁵Ac-DOTA-di-d-Glu-MC1RL (²²⁵Ac-di-d-Glu). The biodistribution (BD) from each was studied and a multicompartment pharmacokinetic (PK) model was developed to describe drug distribution rates. Two groups of 16 severe combined immunodeficient (SCID) mice bearing high MC1R expressing tumors were intravenously injected with ²²⁵Ac-Ahx or ²²⁵Ac-di-d-Glu. After injection, four groups (n = 4) were euthanized at 24, 96, 144, and 288 h time points for each cohort. Tumors and 13 other organs were harvested at each time point. Isomeric γ spectra were measured in tissue samples using a scintillation γ detector and converted to α activity using factors for γ ray abundance per α decay. Time activity curves were calculated for each organ. A five-compartment PK model was built with the following compartments: blood, tumor, normal tissue, kidney, and liver. This model is characterized by a system of five ordinary differential equations using mass action kinetics, which describe uptake, intercompartmental transitions, and clearance rates. The ordinary differential equations were simultaneously solved and fit to experimental data using a genetic algorithm for optimization. The BD data show that both compounds have minimal distribution to organs at risk other than the kidney and liver. The PK parameter estimates had less than 5% error. From these data, ²²⁵Ac-Ahx showed larger and faster uptake in the liver. Both compounds had comparable uptake and clearance rates for other compartments. The BD and PK behavior for two targeted radiopharmaceuticals were investigated. The PK model fit the experimental data and provided insight into the kinetics of the compounds systematically.

中文翻译：

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靶向 α 粒子疗法的生物分布和多室药代动力学分析。

靶向 α 粒子疗法 (TAT) 是治疗疾病的理想选择，同时由于路径长度短和线性能量转移 (LET) 高，可以最大限度地减少对周围非靶向组织的损害。我们开发了一种针对转移性葡萄膜黑色素瘤的 TAT，靶向黑色皮质素 1 受体 (MC1R)，该受体在 94% 的葡萄膜黑色素瘤中表达。正在研究两种版本的疗法：²²⁵ Ac-DOTA-Ahx-MC1RL ( ²²⁵ Ac-Ahx) 和²²⁵ Ac-DOTA-di- d -Glu-MC1RL ( ²²⁵ Ac-di- d-Glu)。研究了每种药物的生物分布 (BD)，并开发了多室药代动力学 (PK) 模型来描述药物分布率。两组 16 只患有高表达 MC1R 肿瘤的严重联合免疫缺陷 (SCID) 小鼠静脉注射²²⁵ Ac-Ahx 或²²⁵ Ac- di - d -Glu。注射后，四组（n= 4) 在每个队列的 24、96、144 和 288 小时时间点被安乐死。在每个时间点收获肿瘤和 13 个其他器官。使用闪烁 γ 探测器在组织样本中测量异构 γ 光谱，并使用每个 α 衰变的 γ 射线丰度因子转换为 α 活性。计算每个器官的时间活动曲线。建立了具有以下区室的五室 PK 模型：血液、肿瘤、正常组织、肾脏和肝脏。该模型的特点是使用质量作用动力学的五个常微分方程系统，这些方程描述了摄取、室间转变和清除率。使用遗传算法进行优化，同时求解常微分方程并拟合实验数据。BD 数据显示，这两种化合物在肾脏和肝脏以外的其他危险器官中的分布极小。PK 参数估计的误差小于 5%。从这些数据来看，²²⁵ Ac-Ahx 在肝脏中显示出更大和更快的吸收。两种化合物对其他隔室具有可比的摄取和清除率。研究了两种靶向放射性药物的 BD 和 PK 行为。PK 模型拟合实验数据并系统地提供对化合物动力学的洞察。