Radioiodinated Multifunctional PARP1 Imaging Probes for Diagnosis and Therapy

项目总结/摘要 该提案的目标是开发一种新的肿瘤细胞消融方法，同时保留健康细胞 活着这种方法是基于123 I，一种放射性碘同位素，发射俄歇电子。俄歇电子 具有在非常窄的半径内耗散其能量的优点，主要限于仅10 纳米。因此，与更常用的α-和β-发射体不同，俄歇电子发射体造成 细胞DNA仅在其靶位点受损，而使邻近的健康细胞不受影响。 我们打算通过将123 I与DNA修复酶PARP 1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输送到 我们已经证明，它们特别适用于递送靶向的 脑肿瘤的有效载荷。这种用途依赖于PARP 1在脑肿瘤中的表达远高于在脑肿瘤中的表达。 周围健康的脑组织此外，俄歇发射PARP 1放射性药物也较少 比α或β放射性核素更可能损害肾脏和肝脏，因为在这些器官中， 绝大多数的活动应该保留在核外，在那里俄歇发射体的毒性 明显较低。 该提议的具体目的是合成放射性碘标记的PARP 1靶向抑制剂的文库， 以确定其中哪种最有可能成功作为俄歇123 I标记的放射治疗剂，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 实验将用于研究全身生物分布和细胞PARP 1表达， DNA损伤治疗后。对于123 I标记的先导化合物，我们将确定广泛的 药效学数据，包括体外和体内。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。将使用浸润性小鼠模型来确定 这种新型放射性药物的潜在影响。我们将进一步设计联合治疗研究， PARP 1俄歇发射器，其中使用亚治疗剂量的外部束辐射来增加活性 和PARP 1的DNA接近，并且治疗剂量用于增加总体PARP 1表达， 这两种作用都增加了肿瘤组织对放射治疗剂的敏感性。 本研究的最终目标是在小鼠模型中验证针对Auger发射体的PARP 1靶向穿梭。 胶质母细胞瘤对于这一应用，一个跨学科的专家团队已经聚集在一起，以帮助在 这项技术的发展。研究小组将包括托马斯雷纳博士（放射化学和探针 Wolfgang Weber博士（核疗法）、罗纳德布拉斯伯格博士（神经病学）和John Humm博士 （医学物理）。研究人员一起组成了一个理想的团队来追求这一新颖的研究途径， 汇集了来自各种学科的专业知识。如果成功，生成的数据将形成 这是MSK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。

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.