Rachel Riley
Graduate Student Rachel Riley will be defending her dissertation on Monday, June 18th at 10:00 am in ISE Lab Room 322.
TITLE:
Nanoshell Platforms for Targeted Gene Regulation and Light-Triggered Cancer Therapy
When: 10:00 am Monday, June 18, 2018
Where: ISE Lab 322
Committee Chair: Dr. Emily Day
Committee: Dr. Jason Gleghorn, Dr. Millicent Sullivan, Dr. Kenneth Van Goen
ABSTRACT: Nanoparticles (NPs) are promising tools to improve upon conventional cancer treatment strategies that are limited by significant off-target effects and unsatisfactory patient outcomes. In this dissertation, we demonstrate that NPs called nanoshells (NSs) comprised of silica cores and thin gold shells are versatile platforms to mediate phototherapy and/or or gene regulation of cancer by exploiting their unique optical and bioconjugation properties. For phototherapies, NSs either generate heat to damage the surrounding cancer cells, or they can be triggered to release any surface-bound molecules using continuous wave or pulsed laser irradiation, respectively. In gene regulation applications, the gold NS surfaces are decorated with therapeutic antibodies or small interfering RNA (siRNA) molecules using gold-thiol chemistry. By exploiting these unique features, our overarching goal was to establish NSs as multifunctional and versatile tools that offer high precision cancer therapy.
Our first objective in this thesis was to evaluate a combinatorial phototherapy approach using both PTT and photodynamic therapy (PDT) to induce irreversible cancer cell death. PTT damages cancer cells by activating NSs embedded in tumors to produce heat in response to near infrared light, while PDT uses photosensitizers that are activated by lower wavelengths of light to produce toxic singlet oxygen. We hypothesized that dual therapy would be more effective for tumor ablation than either therapy alone by overcoming the limitations of each option. In Chapter 3, we evaluate a novel and potent photosensitizer to mediate PDT, and we show that dual PTT/PDT mediated by NSs and this photosensitizer, respectively, work synergistically to induce apoptotic cell death more efficiently than each strategy alone.
Our second objective was to demonstrate that NSs can enable high precision gene regulation through light-triggered release of siRNA. The use of NPs for siRNA delivery is promising to overcome the instability and poor cellular uptake of free siRNA. However, to avoid widespread gene regulation, it is ideal that siRNA-NP conjugates release their cargo on-demand only in tumor cells. We hypothesized that siRNA-NS conjugates would remain inactive until the siRNA was released from NSs upon excitation with pulsed laser light. In Chapter 4, we show that pulsed laser excitation releases duplexes of siRNA, and we provide a mechanistic understanding of how these plasmonic NPs operate to enable on-demand gene regulation.
The third goal was to establish antibody-NS conjugates as platforms for oncogenic cell signaling interference. We hypothesized that antibody-NS conjugates could actively target cancer cells to hinder oncogenic signaling more effectively than freely delivered antibodies due to their higher binding affinities. We found that antibody-NS conjugates bind cancer cells with more strength than free antibodies, resulting in improved signal cascade interference. Further, these conjugates retain their targeting abilities in vivo, as antibody-NS conjugates accumulate in small lung metastases in a murine model of metastatic breast cancer, which slows tumor growth. These results indicate that antibody-NS conjugates may permit lower antibody dosages to be administered for cancer management.
In total, this dissertation evaluates how the unique properties of NSs can be exploited to enable high precision cancer therapy by three powerful but distinct treatment mechanisms. Due to their high specificity and potency, these multifunctional NPs are promising alternatives to current cancer therapies.