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）：放射性核素和放射性核素偶联化学的靶向输送的最新进展，以及适合临床使用的A发射体的可用性增加，最近导致了具有非常有前途的结果的A-Parmiticer标记的放射性药物试验。 NIH的既定目标之一是开发更多个性化的药物。在治疗核医学领域，这转化为需要更准确的个性化剂量法。但是，当前的剂量范式适合于A粒子疗法。这种现实反映在临床（或实验性）毒性之间的巨大差异和使用标准（吸收分数）器官水平的建模和（a）223RA造血疗法的骨转移疗法和（b）在靶向无性药物中的肾脏毒性的毒性的预期毒性。这项工作的目的是创建一个更适合A颗粒发射器的模型。成功完成该提案后，该模型将为目前尚不理解的实验和临床结果提供解释，并为癌症的持续和未来的A粒子疗法提供指导。放射性药物发出的A颗粒的范围为50-80微米。该量表大大比：（a）临床成像探测器和模态的解决力，以及（b）人体器官的规模。当人们认为排放的范围实际上通常是按照一些可能有风险的剂量限制器官的功能或解剖学亚单位的规模，包括肾脏（功能性亚单位：th nephron）和骨髓（骨骨髓的解剖学亚基：骨头：三方），这一点非常重要。此处提出的模型将结合亚单位解剖和动态建模，以准确解释A粒子治疗对潜在剂量限制器官的影响，以进行准确的剂量学和治疗计划。作为第一步，将在Geant4（一种高能量的蒙特卡洛软件（Geant4）中创建相关子单元（Nephron，Marrow腔）的简单几何模型。人类解剖信息将从尸体中收集，以获得解剖精度，并提供一系列反映人类多样性的参数。药代动力学成分将在鼠模型中开发，并将建立宏观测量的整个器官PK到特定的亚单位PK的转化。对人类的翻译假定，在临床模型中测得的给定药物的宏观和显微镜时空关系之间的联系将适用于人类，因为该药物在不同的显微镜隔室中的分布应保持不变。最后，该模型将在鼠MTD实验中进行测试。在鼠实验中的验证与人类模型中个体多样性的潜力的高特异性相结合，将允许在诊所中准确地实现可靠的A粒子剂量测定法。 公共卫生相关性：我们为有风险和肿瘤的器官提出了一个基于细胞和功能亚基的模型，以更准确地评估和预测靶向纳米粒子疗法的反应和毒性。该模型将替代剂量测定的吸收分数范式。临床实施将需要标准的3维SPECT或在多个时间点以类似于当前的剂量学方法的方式进行临床成像。