Development of a Theranostic Nanomedicine Construct for Ovarian Cancer

相关性：卵巢癌是美国女性癌症相关死亡的第五大原因。 虽然卵巢癌患者最初对目前的治疗方案有反应，但大多数患者最终会复发 并产生抗药性疾病。我们的目标是开发一种治疗诊断学，可以检测和分期卵巢癌 同时还充当全身放射性药物递送平台。据设想， 该提案中的技术将允许给予更高的治疗剂量， 这些药剂和其他药物递送系统用于临床的功效、安全性和潜力的增加 翻译. 目的/假设：本提案的目的是开发一种预先靶向治疗诊断平台， 协同地建立在我们的工作与MPS回避，HPMA共聚物，以及利用 IEDDA化学的巨大潜力。我们假设，MPS回避，HPMA共聚物可以作为 作为一个独特的平台，利用这些变革性的体内缀合技术， 一种新的卵巢癌放射治疗剂。 具体目标：（1）优化EPR靶向、MPS规避、HPMA共聚物：调查/优化 影响体外/体内性能的因素;（2）研究和优化小分子 用于体内靶向/偶联至预靶向HPMA共聚物平台的Radioform TZs。 研究设计：在本申请中，我们建议开发一个治疗诊断平台， 组分：1）能够通过EPR效应靶向肿瘤的预靶向诊断HPMA共聚物， 和胃泌素释放肽受体（GRPR），同时有效清除非靶组织，和2）a 放射性示踪剂，使用IEDDA化学，将被肿瘤相关的预靶向的 共聚物在第一个目标中，我们建议优化TCO掺入和GRPR靶向载体密度 以实现所需的生物性能。同时，在第二个目标中， 将对驱逐剂进行调查。在这些研究中，TZ的亲水性的影响 部分将被探索。最后，将使用患者来源的异种移植物研究优化的组分。 卵巢癌的小鼠模型。

RELEVANCE: Ovarian cancer is the fifth leading cause of cancer-related deaths for women in the United States. While ovarian cancer patients initially respond to current treatment options, most patients will eventually relapse and develop drug-resistant disease. Our goal is to develop a theranostic that can detect and stage ovarian cancer while also acting as a systemic radiotherapeutic delivery platform. It is envisioned that the development of the technologies in this proposal would allow for the administration of higher therapeutic doses as well as lead to an increase in the efficacy, safety and potential of these agents, and other drug delivery systems, for clinical translation. OBJECTIVE/HYPOTHESIS: The objective of this proposal is to develop a pretargeted theranostic platform that synergistically builds upon our work with MPS-evading, HPMA copolymers as well as take advantage of the tremendous potential of IEDDA chemistry. We hypothesize that the MPS-evading, HPMA copolymers can serve as a unique platform to exploit these transformative in vivo conjugation technologies in the development of a novel radiotherapeutic agent for ovarian cancer. SPECIFIC AIMS: (1) Optimize the EPR-targeted, MPS-evading, HPMA Copolymers: Investigate/Optimize Factors that Influence In Vitro/In Vivo Performance; (2) Investigate and Optimize Small Molecule Radiotherapeutic TZs for In Vivo Targeting/Conjugation to Pretargeted HPMA Copolymer Platform. STUDY DESIGN: In this application, we propose to develop a theranostic platform composed of two components: 1) a pretargeted diagnostic HPMA copolymer capable of targeting tumors through the EPR effect and the Gastrin-Releasing Peptide Receptor (GRPR), while clearing efficiently from non-target tissues and 2) a radiotherapeutic chaser agent that, using IEDDA chemistry, will be captured by the tumor-associated pretargeted copolymer. In the first aim, we propose to optimize the TCO-incorporation and the GRPR-targeting vector density of the HPMA copolymer to achieve the desired biological performance. Simultaneously, in the second aim, investigations of the chaser agent will be performed. In these studies, the impact of the hydrophilicity of the TZ moiety will be explored. Lastly, the optimized components will be investigated using patient-derived xenograft mouse models of ovarian cancer.