Photoimmunotherapy-Based Combination Regimens and Drug Delivery Systems for Ovarian Cancer Treatment

Abstract

Ovarian cancer is among the deadliest gynecologic malignancies, accounting for over 13,000 deaths and nearly 20,000 new cases each year in the United States alone. The lethality of this disease results from several fundamental challenges, including diagnosis at advanced stages, development of resistance to standard-of-care chemotherapies, and extensive metastasis throughout the peritoneal cavity. Photodynamic therapy (PDT) is a promising treatment modality which enables spatiotemporally controlled cancer ablation upon light-activation of specialized drugs (photosensitizers). Clinical studies have demonstrated the feasibility and safety of PDT for women with peritoneally disseminated ovarian cancer, though treatment outcomes were limited by off-target toxicities and the heterogenous cellular uptake of photosensitizer. The use of antibody-conjugated photosensitizers (photoimmunoconjugates) has the potential to overcome these prior limitations, making the targeted version of PDT (photoimmunotherapy, PIT) a valuable tool for ovarian cancer treatment.The overarching objective of this dissertation is to develop PIT-based strategies for ovarian cancer management through three complimentary goals: 1) overcome metastatic behaviors in ovarian cancer using PIT-based combination therapies; 2) bolster photosensitizer drug delivery using a clinically-relevant, fluid flow-based drug delivery approach; and 3) enhance cytotoxic effects of PIT through developing a new nanocomplex for photochemotherapy. This work establishes novel PIT-based combination treatments that incorporate clinically relevant therapies, including prostaglandin E2 receptor 4 (EP4) antagonism, poly(ADP-Ribose) polymerase (PARP) inhibition, and epidermal growth factor receptor (EGFR)-targeted antibodies. Results from this dissertation reveal pronounced combination effects of PIT and EP4 antagonism, leading to cooperative reductions in metastasis- related behaviors and cell signaling in vitro. The findings of this work further demonstrate that fluid flow enhances photoimmunoconjugate delivery, modulates subcellular photosensitizer localization, and enhances the phototoxicity to ovarian cancer cells in a pump system. Lastly, we developed 1) a targeted nanocomplex for combination of PIT and PARP inhibitors; and 2) a 3- dimentional (3D) ovarian tumor spheroid coculture model for the longitudinal quantification of treatment effects and the development of multidrug resistance.