Modeling Targeted Alpha Particle Therapy of Cancer

癌症靶向阿尔法粒子治疗建模

• 批准号: 8468664
• 负责人: Robert Francois Hobbs
• 金额: $ 29.57万
• 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/8468664
• 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(申请人提供)：在放射性核素和放射性核素结合化学的靶向输送方面的最新进展，以及适用于临床的α-发射体的可用性的增加，最近导致了标记有α-粒子发射体的放射性药物的患者试验，取得了非常有希望的结果。美国国立卫生研究院声明的目标(支柱)之一是开发更个性化的医学；在治疗性核医学领域，这意味着需要更准确的个性化剂量测定。然而，目前的剂量学范例不太适合a粒子治疗。这一现实反映在临床(或实验)毒性和预期毒性之间的巨大差异，这些毒性是使用标准(吸收分数)器官水平建模和剂量学计算得出的，用于(A)223Ra治疗骨转移的血液毒性和(B)在靶向a粒子免疫治疗中的小鼠实验中看到的肾毒性。这项工作的目标是创建一个更适合a粒子发射器的模型。在成功完成该提案后，该模型将为目前尚不了解的实验和临床结果提供解释，并为正在进行的和未来的癌症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微米量级。这一尺度大大小于：(A)临床成像探测器和模式的分辨率，以及(B)人体器官的尺度。考虑到辐射的范围实际上往往是几个可能受到剂量限制的关键器官的功能或解剖亚单位的范围，包括肾脏(功能亚单位：TH肾单位)和骨髓(骨的解剖亚单位：小梁)，第二个是极其重要的。为了准确地解释a粒子治疗对潜在剂量限制器官的影响，以准确地进行剂量测定和治疗计划，这里提出的模型将包括亚单位解剖模型和动态模型。作为第一步，将在高能蒙特卡罗软件GEANT4中创建相关亚单位(肾单位、髓腔)的简单几何模型。人体解剖信息将从身体中收集，以确保解剖学的准确性，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。对人类的转换假设在临床前模型中测量的给定制剂的宏观和微观时空关系之间的联系将适用于人类，因为该制剂到不同微观隔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。在小鼠实验中的验证与人体模型中关于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准确的个性化a粒子剂量测量。