Modeling Targeted Alpha Particle Therapy of Cancer

描述（由申请人提供）：放射性核素和放射性核素缀合化学的靶向递送的最新进展，以及适用于临床使用的α-发射体的可用性增加，最近导致了用α-粒子发射体标记的放射性药物的患者试验，具有非常有希望的结果。NIH的既定目标（支柱）之一是开发更个性化的医学;在治疗核医学领域，这意味着需要更准确的个性化剂量测定。然而，目前的剂量测定范例不太适合α粒子治疗。这一现实反映在临床（或实验）毒性与预期毒性之间的巨大差异上，所述预期毒性使用标准（吸收分数）器官水平建模和剂量测定法计算，用于（a）骨转移的223 Ra治疗中的血液毒性和（B）靶向α粒子免疫治疗中在鼠实验中观察到的肾毒性。这项工作的目的是创建一个模型更适合于a粒子发射器。在成功完成该提案后，该模型将为目前尚未理解的实验和临床结果提供解释，并为正在进行和未来的癌症α粒子治疗提供指导。放射性药物发射的α粒子的范围在50-80微米的量级。该尺度基本上小于：（a）临床成像探测器和模态的分辨能力，以及（B）人体器官的尺度。当考虑到发射的范围实际上通常是处于风险中的几个关键的潜在剂量限制器官的功能或解剖亚单位的规模时，第二个是极其重要的，包括肾脏（功能亚单位：肾单位）和骨髓（骨的解剖亚单位：小梁）。本文提出的模型将结合亚单位解剖以及动态建模，以准确地解释α粒子治疗对潜在剂量限制器官的影响，从而实现准确的剂量测定和治疗计划。作为第一步，将在高能Monte Carlo软件GEANT 4中创建相关亚单位（肾单位、骨髓腔）的简单几何模型。将从尸体中收集人体解剖信息，以确保解剖准确性，并提供一系列反映人体多样性的参数。将在小鼠模型中开发药代动力学组分，并将确定肉眼测量的整个器官PK转换为特定亚单位PK。对人类的翻译假设在临床前模型中测量的给定试剂的宏观和微观时空关系之间的联系将适用于人类，因为试剂到不同微观区室的分布应该保持相同。最后，将在鼠MTD实验中测试该模型。在鼠实验中的验证结合关于人类模型中个体多样性的潜力的高特异性将允许在临床中进行准确的个性化α粒子剂量测定。

DESCRIPTION (provided by applicant): Recent advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of a-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with a-particle emitters with very promising results. One of the stated goals (pillars) of the NIH is to develop more personalized medicine; in the realm of therapeutic nuclear medicine this translates as a need for more accurate personalized dosimetry. However, current dosimetry paradigms are poorly suited to a-particle therapy. This reality is reflected by the vast discrepancies between clinical (or experimental) toxicity and expected toxicity calculated using standard (absorbed fraction) organ-level modeling and dosimetry for (a) hematotoxicity in 223Ra therapy of bone metasteses and (b) renal toxicity seen in murine experiments in targeted a-particle immunotherapy. The objective of this work is to create a model more suited to a-particle emitters. After successful completion of the proposal, this model will provide explanations for experimental and clinical results not currently understood and also provide guidance for ongoing and future a-particle therapy of cancer. The range of the a-particles emitted by the radiopharmaceuticals is on the order of 50-80 microns. This scale is substantially smaller than: (a) the resolving power of clinical imaging detectors and modalities, and (b) the scale of human organs. This second is extremely important when one considers that the range of the emissions is actually often on the scale of the functional or anatomical sub-units of several key potentially dose-limiting organs at risk, including the kidney (functional sub-unit: th nephron), and the bone marrow (anatomical sub-unit of bone: the trabecula). The model proposed here will incorporate both sub-unit anatomical as well as dynamic modeling in order to accurately interpret the effects of a-particle therapy on potential dose-limiting organs for accurate dosimetry and treatment planning. As a first step simple geometrical models of the relevant sub-units (nephron, marrow cavity) will be created in GEANT4, a high-energy Monte Carlo software. The human anatomical information will be gathered from cadavers for anatomical accuracy and provide an array of parameters that reflect human diversity. The pharmacokinetic component will be developed in murine models and the conversion of macroscopically measured whole organ PK to specific sub-unit PK will be established. 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 because the distribution of the agent to the different microscopic compartments should remain the same. Finally, the model will be tested in murine MTD experiments. Validation in the murine experiments combined with the high specificity regarding the potential for individual diversity in the human model will allow for accurate personalizable a-particle dosimetry in the clinic.