Department of Radiology, Johns Hopkins University, Baltimore MD, USA.
Phys Med Biol. 2012 Jul 7;57(13):4403-24. doi: 10.1088/0031-9155/57/13/4403. Epub 2012 Jun 15.
Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. The S-values were calculated for the α-emitters and their descendants between the different nephron compartments for both the human and murine models. The renal cortex and medulla S-values were also calculated and the results compared to traditional absorbed fraction calculations. The nephron model enables a more optimal implementation of treatment and is a critical step in understanding toxicity for human translation of targeted α-particle therapy. The S-values established here will enable a MIRD-type application of α-particle dosimetry for α-emitters, i.e. measuring the TIA in the kidney (or renal cortex) will provide meaningful and accurate nephron-level dosimetry.
靶向α粒子治疗是癌症治疗的一种很有前途的方法。由于α粒子的射程很短，这些药物的潜在疗效和毒性最好通过微尺度剂量学计算来评估，而不是通过整个器官、吸收分数为基础的剂量学来评估。然而，时间积分活性（TIA），剂量学所必需的输入，仍然只能在器官或宏观水平上可靠地定量。我们描述了一种基于肾单位和细胞的肾脏α粒子放射性药物治疗剂量学模型，该模型更适合于α粒子发射体的短射程和高线性能量转移，它以肾脏或皮质 TIA 为输入，通过基于宏观到微观模型的方法将 TIA 分配到微观水平的肾脏子结构。我们应用几何模型为一系列同位素提供肾单位级别的 S 值，根据医学内部辐射剂量学（MIRD）方案，允许进行临床前和临床应用。我们假设，整个器官 TIA 与在适当的临床前哺乳动物模型中测量的分配给微观子结构的 TIA 之间的关系也适用于人类。在临床前和人类模型中，微观子结构被描述为类似于用于正常器官的 Cristy-Eckerman 体模的简单几何形状的集合。解剖参数取自人类模型的文献，而鼠类参数则通过离体测量获得。鼠类组织学幻灯片还提供了肾脏中不同肾单位隔室的容积占有率数据：肾小球与近端肾小管与远端肾小管。对目前正在放射性药物治疗中研究的几种α粒子发射体，用活性物质放置在不同的肾单位隔室中进行蒙特卡罗模拟。为人类和鼠类模型计算了不同肾单位隔室之间的α-发射体及其衍生物的 S 值。还计算了肾脏皮质和髓质的 S 值，并将结果与传统的吸收分数计算进行了比较。肾单位模型能够更好地实施治疗，并在理解靶向α粒子治疗的人类转化毒性方面是一个关键步骤。这里建立的 S 值将使 MIRD 类型的α粒子剂量学应用于α-发射体成为可能，即测量肾脏（或肾皮质）中的 TIA 将提供有意义和准确的肾单位水平剂量学。
