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 并发展出抗药性疾病。我们的目标是开发一种可以检测和分期卵巢癌的治疗药物 同时还充当全身放射治疗输送平台。可以预见的是， 该提案中的技术将允许使用更高的治疗剂量，并导致 提高这些药物和其他药物输送系统的有效性、安全性和潜力，用于临床 翻译。 目标/假设：本提案的目标是开发一种预靶向治疗平台，该平台 协同作用建立在我们与MPS-回避、HPMA共聚物的工作基础上，并利用 IEDDA化学的巨大潜力。我们假设MPS回避的HPMA共聚物可以 作为一个独特的平台来利用这些变革性的体内结合技术来开发 治疗卵巢癌的新型放射治疗剂。 具体目标：(1)优化EPR靶向、MPS规避、HPMA共聚物：调查/优化 影响体内外性能的因素；(2)考察和优化小分子 体内靶向/结合到预靶向HPMA共聚平台的放射治疗TZS。 研究设计：在本申请中，我们建议开发一种由两个 成分：1)能够通过EPR效应靶向肿瘤的预靶向诊断性HPMA共聚物 和胃泌素释放肽受体(GRPR)，同时有效地从非靶组织和2)a)清除 放射治疗追踪剂，使用IEDDA化学，将被肿瘤相关的前靶向捕获 共聚物。在第一个目标中，我们提出了优化TCO掺入和GRPR靶向载体密度的方法 HPMA共聚物以实现所需的生物学性能。同时，在第二个目标中， 将对追踪剂进行调查。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来研究优化的组件。 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.