Radioiodinated Multifunctional PARP1 Imaging Probes for Diagnosis and Therapy

用于诊断和治疗的放射性碘标记多功能 PARP1 成像探针

• 批准号: 9306072
• 负责人: Thomas Reiner
• 金额: $ 50.69万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306072
• 关键词: Ablation; Binding; Binding Proteins; Biodistribution; Biological Assay; Biological Availability; Brain Neoplasms; Cell Line; Cell Membrane Permeability; Cell Nucleus; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Companions; Cytosol; DNA; DNA Damage; DNA Repair Enzymes; Data; Deposition; Development; Diagnosis; Discipline; Dose; Dose-Limiting; Drug Kinetics; Electrons; Excretory function; Exhibits; External Beam Radiation Therapy; Extracellular Space; Failure; Foundations; Future; Gamma Rays; Glioblastoma; Goals; Growth; Hepatocyte; Human; Image; In Vitro; Iodine Isotopes; Ion Transport; Ionizing radiation; Isotopes; Kidney; Label; Lead; Libraries; Linear Energy Transfer; Liver; Malignant - descriptor; Measures; Medical; Metabolic; Metabolism; Modeling; Monitor; Mus; Neurology; Normal tissue morphology; Nuclear; Organ; Patient Care; Pharmacodynamics; Physics; Plasma Proteins; Platelet-Derived Growth Factor; Poly(ADP-ribose) Polymerases; Property; Radial; Radiation; Radiation therapy; Radiation-Sensitizing Agents; Radio; Radioactive; Radioactive Iodine; Radiochemistry; Radioisotopes; Radiopharmaceuticals; Research; Research Personnel; Serum; Site; Specificity; Techniques; Testing; Therapeutic; Time; Tissues; Toxic effect; Tracer; Tumor Cell Nuclei; Tumor Tissue; U251; Validation; Whole Blood; Xenograft Model; Xenograft procedure; base; brain tissue; cancer cell; cell growth; cellular targeting; chemotherapy; design; experimental study; fluorescence imaging; imaging agent; imaging probe; in vivo; inhibitor/antagonist; intravital imaging; killings; lipid solubility; molecular targeted therapies; mouse model; nanometer; neoplastic cell; novel; novel strategies; novel therapeutics; nuclear imaging; pre-clinical; radiosensitizing; radiotracer; research and development; residence; single photon emission computed tomography; small molecule; success; systemic toxicity; targeted delivery; technology development; tumor; tumor DNA; tumor growth; uptake; vector

Project Summary/Abstract The goal of this proposal is to develop a novel approach for tumor cells ablation, while leaving healthy cells alive. This approach is based on 123I, a radioactive iodine isotope that emits Auger electrons. Auger electrons have the advantage of dissipating their energy in a very narrow radius, principally confined to only 10 nanometers. Therefore, unlike the more commonly used α- and β-emitters, Auger electron emitters inflict cellular DNA damage only at their targeted site, while leaving healthy cells in the immediate vicinity unaffected. We intend to target the DNA of cancer cells by conjugating 123I to inhibitors of the DNA repair enzyme PARP1. In preliminary experiments, we have shown these agents can efficiently transport ionizing radiation into the nuclei of cancer cells, and we have demonstrated that they are particularly useful for the delivery of targeted payloads to brain tumors. This use relies on the expression of PARP1 in brain tumors being far higher than in the healthy surrounding brain tissue. In addition, Auger emitting PARP1 radiopharmaceuticals are also less likely to damage kidney and liver than α- or β-emitting radionuclides, because in those organs, the overwhelming amount of activity should be retained outside of the nucleus, where the toxicity of Auger emitters is significantly lower. The Specific Aims of this proposal are to synthesize a library of radioiodinated PARP1 targeted inhibitors, and to determine which of them will most likely be successful as Auger 123I-labeled radiotherapeutics, based on their bioavailability, metabolic stability, tissue concentrations and residence times. Parallel SPECT imaging experiments will be used to study the whole body biodistribution and cellular PARP1 expression before and after DNA damaging treatment. For the 123I-labeled lead compound, we will determine extensive pharmacodynamic data, both in vitro as well as in vivo. We will perform a dose escalation study, and measure the effects on tumor growth and systemic toxicity. Infiltrative mouse models will be used to determine the potential impact of this novel radiotherapeutic drug. We will further design combination treatment studies with PARP1 Auger emitters, where sub-therapeutic doses of external beam radiation are used to increase activity and DNA proximity of PARP1, and therapeutic doses are used to increase overall PARP1 expression, with both effects increasing the sensitivity of tumor tissue to the radiotherapeutics. The ultimate goal of this study is to validate PARP1 targeted shuttles for Auger emitters in mouse models of glioblastoma. For this application, an interdisciplinary team of experts has been brought together to aid in the development of this technology. The research team will include Dr. Thomas Reiner (Radiochemistry and Probe Development), Dr. Wolfgang Weber (Nuclear Therapy), Dr. Ronald Blasberg (Neurology) and Dr. John Humm (Medical Physics). Together, the investigators form an ideal team to pursue this novel research avenue, bringing together expertise from a wide variety of disciplines. If successful, the generated data will form the foundation for a future clinical trial at MSK, directly impacting patient care and treatment of glioblastoma.

项目概要/摘要 该提案的目标是开发一种消融肿瘤细胞的新方法，同时保留健康细胞 活。这种方法基于 123I，一种发射俄歇电子的放射性碘同位素。俄歇电子 具有在非常窄的半径内耗散能量的优点，主要限于 10 纳米。因此，与更常用的 α 和 β 发射器不同，俄歇电子发射器会造成 细胞DNA仅在目标位点受损，而附近的健康细胞不受影响。 我们打算通过将 123I 与 DNA 修复酶 PARP1 的抑制剂结合来靶向癌细胞的 DNA。 在初步实验中，我们已经证明这些试剂可以有效地将电离辐射传输到 癌细胞的细胞核，我们已经证明它们对于递送靶向药物特别有用 脑肿瘤的有效负载。这种用途依赖于 PARP1 在脑肿瘤中的表达远高于在脑肿瘤中的表达。 健康的周围脑组织。此外，俄歇发射的PARP1放射性药物也较少 与α或β发射放射性核素相比，它更可能损害肾脏和肝脏，因为在这些器官中， 绝大多数的活性应该保留在细胞核之外，在那里俄歇发射器的毒性 明显较低。 该提案的具体目标是合成放射性碘标记的 PARP1 靶向抑制剂库，以及 确定其中哪一种最有可能成功作为 Auger 123I 标记的放射治疗药物，基于 它们的生物利用度、代谢稳定性、组织浓度和停留时间。并行 SPECT 成像 实验将用于研究前后的全身生物分布和细胞PARP1表达 DNA损伤处理后。对于 123I 标记的先导化合物，我们将确定广泛的 体外和体内的药效学数据。我们将进行剂量递增研究并测量 对肿瘤生长和全身毒性的影响。浸润性小鼠模型将用于确定 这种新型放射治疗药物的潜在影响。我们将进一步设计联合治疗研究 PARP1 俄歇发射器，使用亚治疗剂量的外部光束辐射来增加活性 和 PARP1 的 DNA 接近度，并且使用治疗剂量来增加 PARP1 的整体表达，其中 这两种作用都会增加肿瘤组织对放射治疗的敏感性。 本研究的最终目标是在小鼠模型中验证 PARP1 靶向穿梭机用于俄歇发射器 胶质母细胞瘤。对于此应用程序，我们聚集了一个跨学科的专家团队来帮助 这项技术的发展。该研究团队将包括 Thomas Reiner 博士（放射化学和探针） 开发）、Wolfgang Weber 博士（核治疗）、Ronald Blasberg 博士（神经病学）和 John Humm 博士 （医学物理学）。研究人员共同组成了一个理想的团队来追求这一新颖的研究途径， 汇集来自各个学科的专业知识。如果成功，生成的数据将形成 为 MSK 斯隆未来的临床试验奠定了基础，直接影响胶质母细胞瘤的患者护理和治疗。