Modeling Targeted Alpha Particle Therapy of Cancer

癌症靶向阿尔法粒子治疗建模

• 批准号: 8658040
• 负责人: Robert Francois Hobbs
• 金额: $ 31.11万
• 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/8658040
• 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.

描述（由申请人提供）：放射性核素靶向递送和放射性核素偶联化学的最新进展，以及适合临床使用的a-发射器的可用性的增加，最近导致了用a-粒子发射器标记的放射性药物的患者试验，结果非常有希望。美国国立卫生研究院的一个既定目标（支柱）是开发更加个性化的医疗；在治疗性核医学领域，这意味着需要更精确的个性化剂量测定。然而，目前的剂量学模式并不适合于a粒子治疗。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法计算的预期毒性之间存在巨大差异，这反映了这一现实(a) 223Ra治疗骨转移的血液毒性和(b)靶向a粒子免疫治疗小鼠实验中的肾毒性。这项工作的目标是创建一个更适合于a粒子发射体的模型。在提案成功完成后，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a粒子治疗提供指导。放射性药物释放的a粒子的范围约为50-80微米。这个尺度大大小于：(a)临床成像探测器和模式的分辨能力，以及(b)人体器官的尺度。当人们考虑到辐射的范围实际上通常在几个关键的潜在剂量限制器官的功能或解剖亚单位的范围内，包括肾脏（功能亚单位：肾元）和骨髓（骨的解剖亚单位：小梁），这第二点是极其重要的。本文提出的模型将结合亚单位解剖学和动力学建模，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，相关亚单位（肾元、骨髓腔）的简单几何模型将在高能蒙特卡罗软件GEANT4中创建。人体解剖信息将从尸体中收集，以提高解剖精度，并提供一系列反映人类多样性的参数。将在小鼠模型中开发药代动力学成分，并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，因为药剂在不同微观隔间中的分布应该保持不变。最后，该模型将在小鼠MTD实验中进行验证。在小鼠实验中进行验证，并结合人类模型中个体多样性潜力的高特异性，将允许在临床中进行精确的个性化a粒子剂量测定。