Radioiodinated Multifunctional PARP1 Imaging Probes for Diagnosis and Therapy

项目摘要/摘要 这项提议的目标是开发一种新的方法来消融肿瘤细胞，同时保留健康细胞 活着。这种方法是基于123I，这是一种发射俄歇电子的放射性碘同位素。俄歇电子 他们的优势是在非常窄的半径内消耗能量，主要限制在10 纳米级。因此，与更常用的α和β发射器不同，俄歇电子发射器 细胞DNA只在目标部位受损，而邻近的健康细胞不受影响。 我们打算通过将123I与DNA修复酶PARP1的抑制剂偶联来靶向癌细胞的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靶向递送特别有用 脑瘤的有效载荷。这一用途依赖于PARP1在脑肿瘤中的表达远远高于 周围健康的脑组织。此外，俄歇发射的PARP1放射性药物也较少 对肾脏和肝脏的损害比释放α或β的放射性核素更有可能，因为在这些器官中， 绝大多数的活动应该保留在原子核之外，在那里俄歇发射器的毒性 要低得多。 这项建议的具体目标是合成一个放射性碘标记的PARP1靶向抑制剂的文库，以及 为了确定其中哪一种最有可能作为Auger 123I标记的放射治疗药物成功，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 实验将用来研究前和后的全身生物分布和细胞PARP1的表达 在DNA损伤治疗之后。对于123I标记的铅化合物，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。将使用浸润性小鼠模型来确定 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，其中使用亚治疗剂量的外束辐射来增加活性 和PARP1的DNA接近，以及治疗剂量用于增加总体PARP1的表达， 这两种作用都增加了肿瘤组织对放射治疗的敏感性。 这项研究的最终目标是在小鼠模型中验证PARP1靶向航天飞机的俄歇发射器 胶质母细胞瘤。对于这项申请，已经召集了一个跨学科的专家团队来帮助 这项技术的发展。研究小组将包括Thomas Reiner博士(放射化学和探测器 发展)、沃尔夫冈·韦伯博士(核疗法)、罗纳德·布拉斯伯格博士(神经病学)和约翰·哈姆博士 (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， 汇集了各行各业的专业知识。如果成功，生成的数据将形成 为MSK未来的临床试验奠定基础，直接影响到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.