Development of a Theranostic Nanomedicine Construct for Ovarian Cancer

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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.