Macro-to-micro (M2µ) Activity Apportionment for αRPT

放射性核素靶向输送的最新进展和适当增加的发射体的可用性 临床使用导致了多α发射体放射药物疗法(RPTS)的患者试验。其中之一 这些，Xofigo(223RaCl2)已获得FDA批准，并处于常规临床实践中，许多其他药物可能会效仿。 美国国立卫生研究院声明的目标(支柱)之一是在医学上实现更高水平的个性化。在…的领域 放射药物治疗(RPT)这直接转化为对更准确的个性化剂量测定的需求 以便能够为每个患者量身定做分级和管理活动。然而，目前的剂量学 范例不太适合RPT。这一现实反映在临床(或 实验)毒性和使用标准器官水平(或体素水平)剂量学计算的预期毒性， 包括：(A)223Ra治疗骨转移的血液毒性；(B)肾脏和唾液腺 临床前模型和患者的毒性。这项工作的目标是创建一种更多的剂量学方法 适用于αRPT，即宏观到微观(M2)方法，它要求对子器官活动进行分配 处于危险中的器官的因素。这将通过以下目标来实现：1.在小鼠模型中，测量αRPT 选定的整个器官和相关器官分区的活性浓度；产生分摊系数 直方图。对人类的翻译假设宏观和微观之间的联系 在临床前模型中测量的给定制剂的时空关系将应用于人类，作为 药剂分配到不同的微观隔间应保持不变。我们将测试和 量化这一假设的有效性，并通过引入第三个物种来改进人类分摊系数， 目标2中的小型猪。我们将评估分摊系数的可转移性，通过获得相应的 猪模型的分配因子直方图。在目标3中，我们将演示M2µ可以预测 猪的模型。4.将M2µ方法应用于临床试验数据，以量化 个性化的M2微剂量测量和/或得出剂量-反应关系。成功完成建议书 将协调目前尚不了解的实验和临床结果，并提供强大的标准化 基于剂量学的个性化α放射治疗计划的剂量学研究。这种标准化将使 剂量测量应归一化为EQD2，从而能够与其他RPT或外部射束进行合理组合 治疗以及相关的吸收剂量报告。在这里，我们计划将此方法扩展为包含 广泛的RPT/器官组合，已被证明或可能具有剂量限制和 这需要宏观到微观(M2)方法来适当地将剂量测定与毒性阈值相关联，并 提供可交付成果，使最终用户能够将宏观衡量的活动转换为标准化活动 在器官和(临床相关的)亚器官水平上对广泛的RPT进行剂量测定，并相应地 相关器官。

Recent advances in the targeted delivery of radionuclides and the increased availability of -emitters appropriate for clinical use have led to patient trials of multiple α-emitter radiopharmaceutical therapeutics (RPTs). One of these, Xofigo (223RaCl2) was FDA-approved and is in routine clinical practice, with many others likely to follow. One of the stated goals (pillars) of the NIH is a greater level of personalization in medicine. In the realm of radiopharmaceutical therapy (RPT) this translates directly as a need for more accurate personalized dosimetry in order to enable fractionation and administered activity tailored to each patient. However, current dosimetry paradigms are poorly suited to RPT. This reality is reflected by the discrepancies between clinical (or experimental) toxicity and expected toxicity calculated using standard organ-level (or voxel-level) dosimetry, including most notably: (a) hematotoxicity in 223Ra therapy of bone metastases, (b) renal and salivary gland toxicity in pre-clinical models and patients. The objective of this work is to create a dosimetric methodology more suited to αRPT, namely the Macro to micro (M2) methodology, which requires sub-organ activity apportionment factors for organs at risk. This will be accomplished via the following Aims: 1. In murine models, measure αRPT activity concentration in selected whole organs and in relevant organ sub-regions; generate apportionment factor histograms. The translation to human assumes that the link between macroscopic and microscopic spatiotemporal relationship for a given agent measured in a pre-clinical model will apply to the human as the distribution of the agent to the different microscopic compartments should remain the same. We will test and quantify the validity of this assumption and refine the human apportionment factors by introducing a third species, the mini-pig In Aim 2. We will assess apportionment factor transferability, by obtaining corresponding apportionment factor histograms for a porcine model. In Aim 3. We will demonstrate that M2µ predicts toxicity in the porcine model. 4. Apply the M2µ methodology to clinical trial data to quantify the potential benefit of personalized M2µ dosimetry and/or derive dose–response relationships. Successful completion of the proposal will reconcile experimental and clinical results not currently understood and provide a robust standardized dosimetry for personalized dosimetry-based treatment planning of αRPT. Such standardization will enable the dosimetry to be normalized to EQD2, thus enabling rational combinations with other RPTs or external beam therapy as well as relevant absorbed dose reporting. Here we plan to expand this approach to encompass the wide range of RPT/organ combinations that have either been shown to be or are potentially dose-limiting and that require the Macro to micro (M2) methodology to properly correlate dosimetry with toxicity thresholds and provide a deliverable that will allow end-users to convert macroscopically-measured activity to standardized dosimetry at the organ and (clinically relevant) sub-organ-level for a wide range of RPTs and correspondingly relevant organs.