| Popis: |
Each year, one million new cases of cancer are diagnosed in the United States and each case is unique, making it hard disease to prevent and treat. In the past few decades, nanoparticles have emerged as a promising platform for the development of cancer therapies. Unlike small molecule drugs, nanoparticles can be both passively and actively targeted towards tumor sites (both primary and metastatic sites). Additionally, they are able to carry large cargos for delivery of monotherapy or combination therapy, while also decreasing systemic side effects often associated with small molecule cancer therapies. Nanoparticles in the clinic, as well as in clinical and pre-clinical trials have been predominantly spherical in shape. However, recent data suggest that high aspect ratio nanoparticles may have advantages for cancer treatment, including decreased uptake by phagocytic cells, improved margination, and enhanced tumor homing and penetration. Despite this, synthesis of these materials remains challenging using chemical approaches. Therefore, I turned to towards the study of plant virus-based nanoparticles, and my dissertation focused on the study and development of high aspect ratio viral nanoparticles. Specifically, I focused on the plant viruses tobacco mosaic virus (TMV) and potato virus X (PVX). My initial studies evaluated TMV as a model high aspect ratio nanoparticle and determined that it had improved diffusion into a 3D spheroid compared to a spherical virus. Additionally, I determined that it could be stably loaded with via non-covalent interactions with a cationic photosensitizer for photodynamic therapy. In the central body of my thesis I developed the filamentous virus PVX for cancer therapy. Stealth coated PVX filaments exhibited substantially extended circulation time, while also decreasing recognition by PVX-specific antibodies, an important step towards translation of this platform. Addition of targeting ligands on the surface of the PVX filament led to selective targeting of cells in mono- and co-culture. Finally, a chemotherapy-loaded PVX filament was evaluated in in vitro and in vivo models of cancer and showed promise as a drug delivery platform for intravenous administration, as well as an intratumoral chemoimmunotherapy. Overall, my research enhanced the understanding of high aspect ratio viral nanoparticles, and described the development of a filamentous platform technology for cancer therapy. It has laid groundwork towards the development of improved and effective high aspect ratio virus-based cancer therapies. |
