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

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dc.contributor.advisorHuang, Huang Chiaoen_US
dc.contributor.authorSorrin, Aaronen_US
dc.contributor.departmentBioengineeringen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2023-10-10T05:32:27Z
dc.date.available2023-10-10T05:32:27Z
dc.date.issued2023en_US
dc.description.abstractOvarian 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.en_US
dc.identifierhttps://doi.org/10.13016/dspace/iblm-yqib
dc.identifier.urihttp://hdl.handle.net/1903/30897
dc.language.isoenen_US
dc.subject.pqcontrolledBioengineeringen_US
dc.subject.pquncontrolledFluid Shear Stressen_US
dc.subject.pquncontrolledOvarian Canceren_US
dc.subject.pquncontrolledPARP Inhibitoren_US
dc.subject.pquncontrolledPhotodynamic Therapyen_US
dc.subject.pquncontrolledPhotoimmunoconjugateen_US
dc.subject.pquncontrolledPhotoimmunotherapyen_US
dc.titlePhotoimmunotherapy-Based Combination Regimens and Drug Delivery Systems for Ovarian Cancer Treatmenten_US
dc.typeDissertationen_US

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