ENGINEERING LIGHT-ACTIVATABLE NANOCOMPLEX TO OVERCOME MULTIDRUG RESISTANCE AND IMPROVE DRUG DELIVERY

Abstract

Chemotherapy remains the main strategy for combating cancer, despite significant advances in alternative treatment modalities. It has been estimated that up to 90% of cancer-related deaths are caused by chemotherapy failure due to cancer multidrug resistance (MDR). MDR is a cellular phenomenon where cells are able to evade drug-induced cell death by developing resistance to multiple structurally and mechanistically distinct therapeutic compounds. Insufficient drug delivery, activation of compensatory survival pathways, and enhanced drug efflux by ATP-binding cassette (ABC) drug transporters are the primary challenges underlying MDR. As a result, an ideal cancer treatment strategy should involve selective delivery, retention, and activation of multiple therapeutic agents at the diseased site.Photodynamic therapy (PDT) is a photochemistry-based treatment modality that has shown promise in overcoming cancer drug resistance due to its unparalleled spatiotemporal control over treatment induction using light. The overall objective of this dissertation is to combine engineering strategies and PDT to overcome the existing challenges of MDR. The findings from this dissertation reveal PDT photochemically inactivates ABC drug transporters via functional (i.e., ATPase activity) inhibition and protein structural damage in a dose dependent manner. Our data suggest conjugation of a photosensitizer to conformation-sensitive antibody enables selective photosensitizer delivery to drug-resistant cancer cells and fluorescence visualization of functionally active ABC drug transporters. Our findings further show that targeted nanotechnology can improve photosensitizer delivery and allow for multidrug packaging for PDT-based combination treatment. Lastly, we leverage a dual fluorescence-guided approach to monitor the biodistribution of a targeted nanoformulation and customize intraoperative PDT dosimetry in vivo. Together, these findings from this dissertation advance the current understanding on using a light-activatable strategy to combat cancer drug resistance in three major ways: 1) elucidating the mechanism underlying photochemical inactivation of ABC drug transporters, 2) providing novel engineering strategies to improve multidrug delivery to cancer cells, and 3) demonstrating fluorescence-guided drug delivery and PDT light dosimetry.