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

基本信息

批准号：
9177196
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
项目类别：
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/9177196
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 Ionizing radiation Isotopes Kidney Label Lead Left Libraries Life 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 Radio Radioactive Radioactive Iodine Radiochemistry Radioisotopes Radiopharmaceuticals Research Research Personnel Serum Site Specificity Techniques Testing Therapeutic Time Tissues Toxic effect Tracer Tumor Tissue U251 Validation Whole Blood Xenograft Model Xenograft procedure abstracting base brain tissue cancer cell cell growth chemotherapy design fluorescence imaging imaging agent imaging probe in vivo inhibitor/antagonist intravital imaging killings lipid solubility mouse model nanometer neoplastic cell novel novel strategies novel therapeutics pre-clinical radiosensitizing radiotracer research study residence single photon emission computed tomography small molecule success systemic toxicity targeted delivery technology development tumor tumor DNA tumor growth uptake vector

项目摘要

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.

项目摘要/摘要该建议的目的是开发一种新型的肿瘤细胞消融方法，同时留下健康的细胞活。这种方法基于123i，这是一种放射螺旋电子电子的放射性碘同位素。具有在非常狭窄的半径中消散能量的优势，主要仅限于10 纳米。因此，与更常用的α-和β发射器不同，螺旋钻电子发射器会造成细胞DNA仅在其目标部位损害，同时将健康细胞留在附近不受影响。我们打算通过将123I与DNA修复酶PARP1的抑制剂结合到癌细胞的DNA。在初步实验中，我们表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靶向的递送特别有用有效载荷给脑肿瘤。这种使用依赖于脑肿瘤中PARP1的表达远高于周围健康的脑组织。此外，发射PARP1放射性药物也较少可能会损害肾脏和肝脏比α-或β发射放射性的，因为在那些器官中压倒性的活性应保留在核之外，螺旋螺旋发射器的毒性明显较低。该提案的具体目的是合成一个放射性施工PARP1靶向抑制剂的库，以及确定其中哪些最有可能作为基于123i标记的放射线剂成功的成功它们的生物利用度，代谢稳定性，组织浓度和停留时间。平行SPECT成像实验将用于研究整个身体的生物分布和细胞PARP1表达和细胞的表达 DNA破坏治疗后。对于123i标记的铅化合物，我们将确定广泛的在体外和体内都有药物动态数据。我们将进行剂量升级研究，并测量对肿瘤生长和全身毒性的影响。渗透鼠标模型将用于确定这种新型放射治疗药物的潜在影响。我们将进一步设计与 PARP1螺旋钻发射器，其中使用亚治疗剂量的外束辐射来增加活动 PARP1的DNA接近度以及治疗剂量用于增加总体PARP1表达，并具有两种影响都会增加肿瘤组织对放射性疗法的敏感性。这项研究的最终目的是验证鼠标模型中的螺旋螺旋射台的PARP1靶向班车胶质母细胞瘤。对于此应用，一支跨学科的专家团队已经聚集在一起这项技术的开发。研究小组将包括托马斯·雷纳（Thomas Reiner）博士（放射化学和探测）发展），沃尔夫冈·韦伯（Wolfgang Weber）博士（核治疗），罗纳德·布拉斯伯格（Ronald Blasberg）博士（神经病学）和约翰·汉姆（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，以追求这座新颖的研究途径，将各种学科的专业知识汇集在一起。如果成功，生成的数据将形成在MSK进行未来临床试验的基础，直接影响胶质母细胞瘤的患者护理和治疗。