| Ovarian cancer is the fourth leading cause of death in women of developed countries, with dismal survival improvements achieved in the past three decades. Specifically, current chemotherapy strategies for second-line treatment of relapsed ovarian cancer are unable to effectively treat recurrent disease. This thesis aims to improve the therapeutic outcome associated with recurrent ovarian cancer by (1) creating a 3D cell screening method as an in vitro model of the disease (2) developing a nanomedicine of doxorubicin (DOX) that is more efficacious than PEGylated liposomal doxorubicin (PLD / Doxil RTM ) and (3) evaluating additional strategies to enhance treatment efficacy such as mild hyperthermia (MHT) and combination therapy with inhibitors of the poly(ADP-ribose) polymerase enzyme family (PARP). Overall, this work demonstrates the use of 3D multicellular tumor spheroids (MCTS) as an in vitro drug testing platform which more closely reflects the clinical presentation of recurrent ovarian cancer relative to traditional monolayer cultures. With the use of this technology, it was found that tissue penetration of drug is not only an issue for large tumors, but also for invisible, microscopic lesions that result from metastasis or remain following cytoreductive surgery. A novel block-copolymer micelle formulation for DOX was developed and fulfilled the goal of iicontrolling drug release while enhancing intratumoral distribution and MCTS bioavailability of DOX, which resulted in a significant improvement in growth inhibition, relative to PLD. MHT appeared to enhance drug accumulation in MCTS in the short term, but not after 48 h of drug treatment. Drug combination studies of DOX together with the PARP inhibitor, olaparib (OLP, Lynparza RTM ) were conducted in 2D monolayers and 3D MCTS. In these studies, the effectiveness of the DOX:OLP combination therapy in monolayers and MCTS was found to be ratio dependent such that equimolar ratios resulted in an additive effect, while a greater level of synergy was observed with more extreme ratios. The synergistic effect observed bears promise for future evaluation in vivo which warrants an appropriate delivery method to ensure that the determined molar ratios of both drugs accumulate at the tumor as such, despite differences in the pharmacokinetic profile of each drug, respectively. |
