Polymer Nanoparticle Design for Ovarian Cancer Therapies
Snyder, Catherine
2021
Abstract
Ovarian cancer is the fifth leading cause of cancer related death in females and current clinical treatments have low patient survival rates. Nanoparticle drug delivery has been promoted as an effective therapy, however very few nanoformulations are translated from the lab to the clinic. This absence of successful nanoparticles is partially due to: 1) a lack of understanding of how nanoparticle properties impact in vivo biodistribution, 2) nanoparticle design which does not consider the multi-faceted tumor microenvironment (TME), and 3) reliance on chemotherapeutics which cause harsh side effects. My work addressed these shortcomings by designing polymer nanoparticles for improving ovarian cancer treatments. The first aim was to develop wettability engendered templated self-assembly (WETS), a polymer particle fabrication method. This technique can produce monodisperse, spherical and non-spherical multiphasic particles in a range of 25 nm to 150 µm with up to 7 phases. The size, planar geometry and composition of each phase can be independently altered in non-spherical particles which can be reconfigured into spherical particles. WETS is the first technique which has clearly defined predictive models that allow for the fabrication of extremely varied particles with a single method. With continued work focused on the scale up of WETS, this method could enable the undertaking of a systematic study of particle properties in vivo. A survey of particle biodistribution based on size, shape and composition would improve the understanding of nanoparticle drug delivery. Additionally, ideal particle properties for cancer therapies could be identified, thus removing dependance on the rarely observed enhanced permeability and retention effect. The second aim focused on developing a co-delivery nanoparticle therapy that addresses the supportive nature of non-cancerous mesenchymal stem cells (MSC) in the TME. MSC have been shown to increase cancer stem cells (CSC) chemoresistance and metastasis, and this effect is generally ignored in the design of nanoparticles for drug delivery. Polymer nanoparticles fabricated with electrospraying were demonstrated to encapsulate both paclitaxel and sunitinib with a diameter of 150-200 nm. Delivery of sunitinib as a free drug was shown to disrupt CSC stemness and migration due to MSC co-culture, and co-delivery of sunitinib and paclitaxel was more effective in causing CSC death. This identifies paclitaxel and sunitinib as a possible co-delivery nanoparticle therapy for future studies. Finally, the third aim investigated α-terpineol (αT), one of the active components of tea tree oil, as a chemotherapeutic for ovarian cancer. αT was found to be more specific in killing ovarian cancer cells as opposed to non-cancerous cells and was able to be encapsulated within an electrosprayed polymer nanoparticle (150-200 nm). Continued work in developing an αT-conjugated polymer could lead to the fabrication of a slow-release formulation with a higher initial αT loading which is hypothesized to be more effective. In summary, my PhD work has created innovative polymer nanoparticle technologies and therapeutic approaches to kill ovarian cancer cells and improve cure rates. The unique and highly versatile polymer particle fabrication method, WETS, was developed and can contribute extensively to the understanding of nanoparticle behavior in vivo. Additionally, investigation into the combination treatment of paclitaxel and sunitinib, as well as αT was carried out which can provide insight to future ovarian cancer therapies. This work reflects the integration of concepts from surface science, polymer and cancer bioengineering in pursuit of eradicating ovarian cancer.Deep Blue DOI
Subjects
Nanoparticle Drug Delivery Ovarian Cancer Electrospray
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