Modeling Targeted Alpha Particle Therapy of Cancer

癌症靶向阿尔法粒子治疗建模

• 批准号: 8295112
• 负责人: Robert Francois Hobbs
• 金额: $ 33.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-10 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295112
• 关键词: 3-Dimensional; Accounting; Alpha Particles; Anatomy; Body Regions; Bone Marrow; Cadaver; Cell Cycle Kinetics; Cell Mobility; Cells; Chemistry; Clinic; Clinical; Computer software; Daughter; Diffusion; Discipline of Nuclear Medicine; Dose; Dose-Limiting; Drug Kinetics; Future; Goals; Human; Immunotherapy; Individual; Isotopes; Kidney; Kinetics; Label; Length; Life Cycle Stages; Link; Literature; Marrow; Measurement; Measures; Medicine; Methodology; Microscopic; Modeling; Mus; Nephrons; Organ; Organ Model; Patients; Pelvis; Physiological; Positron-Emission Tomography; Pre-Clinical Model; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Red Marrow; Risk; Sampling; Specificity; Testing; Theoretical model; Therapeutic; Therapeutic Uses; Time; Toxic effect; Translating; Translations; United States National Institutes of Health; Validation; Work; base; bone; cancer therapy; density; dosimetry; human data; imaging detector; imaging modality; improved; in vivo Model; interest; nanoparticle; particle; research study; response; rib bone structure; single photon emission computed tomography; spatiotemporal; spine bone structure; substantia spongiosa; targeted delivery; tissue repair; treatment planning; tumor

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. PUBLIC HEALTH RELEVANCE: We propose a cellular and functional sub-unit based model for organs at risk and tumors for a more accurate assessment and prediction of response and toxicity in targeted nanoparticle therapy of cancer. This model will replace the absorbed fraction paradigm of dosimetry for ?-emitters. Clinical implementation will require standard 3-dimensional SPECT or PET imaging at multiple time points in an analogous manner to current dosimetric methodologies.

描述（由申请人提供）：放射性核素的靶向递送和放射性核素共轭化学的最新进展，以及适合临床使用的α-发射体的可用性的增加，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）之一是开发更加个性化的医疗；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，当前的剂量测定范式不太适合α粒子治疗。这一现实反映在临床（或实验）毒性与使用标准（吸收分数）器官水平模型和剂量测定计算的预期毒性之间存在巨大差异，其中（a）223Ra治疗骨转移中的血液毒性和（b）在骨转移中观察到的肾毒性靶向α粒子免疫疗法的小鼠实验。这项工作的目标是创建一个更适合 a 粒子发射器的模型。该提案成功完成后，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粒子的范围约为50-80微米。该规模远小于：(a) 临床成像探测器和模式的分辨率，以及 (b) 人体器官的规模。当人们考虑到排放范围实际上通常是处于危险中的几个关键潜在剂量限制器官的功能或解剖亚单位的规模时，第二点极其重要，包括肾脏（功能亚单位：肾单位） ）和骨髓（骨的解剖亚单位：小梁）。这里提出的模型将结合子单元解剖学和动态建模，以便准确解释a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，将在高能蒙特卡罗软件 GEANT4 中创建相关子单元（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，并提供反映人类多样性的一系列参数。将在小鼠模型中开发药代动力学成分，并将建立宏观测量的整个器官 PK 到特定亚单位 PK 的转换。对人类的翻译假设在临床前模型中测量的给定药剂的宏观和微观时空关系之间的联系将适用于人类，因为药剂到不同微观区室的分布应该保持相同。最后，该模型将在小鼠 MTD 实验中进行测试。小鼠实验的验证与人类模型中个体多样性潜力的高度特异性相结合，将允许在临床上进行精确的个性化 a 粒子剂量测定。 公共健康相关性：我们提出了一种基于细胞和功能亚单位的模型，用于危险器官和肿瘤，以便更准确地评估和预测癌症靶向纳米颗粒治疗的反应和毒性。该模型将取代 β 发射体剂量测定的吸收分数范例。临床实施将需要在多个时间点以与当前剂量测定方法类似的方式进行标准 3 维 SPECT 或 PET 成像。