The development of photoactivated nanoparticles for therapeutic miRNA delivery to selectively induce apoptosis in cancer cells
Restricted (Penn State Only)
- Author:
- Liu, Yiming
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 25, 2022
- Committee Members:
- Adam Glick, Outside Unit & Field Member
Pak Kin Wong, Major Field Member
Jian Yang, Major Field Member
Daniel Hayes, Chair & Dissertation Advisor
Daniel Hayes, Program Head/Chair
Jian Yang, Major Field Member - Keywords:
- microRNAs
retro-Diels-Alder
Immunomodulation
Nanoparticle
Cancer therapy - Abstract:
- Common treatments for cancer such as surgical resection, chemotherapy and radiation induce severe side effects. Current immunotherapy and targeted therapy can be effective against certain types of cancer, but still result in reduced specificity and increased toxicity. In addition, Tumors are often heterogenic and likely to develop drug resistance over time. There is a critical need for novel therapeutics which can selectively induce apoptosis in cancer cells while reducing side effects for adjacent normal tissues. MicroRNAs (miRNAs) are short single-stranded non-coding RNAs that negatively regulate gene expression and many studies have shown that the deregulation of miRNAs has been associated with tumorigenesis. Thus, delivering tumor-suppressive miRNAs to cancer cells has the potential to improve current treatments. However, a major challenge is to achieve spatiotemporal control in order to avoid off-target gene silencing. Therefore, we have developed two different metallic photoactivated nanoparticle systems for delivering functional miRNA mimics to treat epidermal squamous cell carcinomas and glioblastoma (GBM). With Silver nanoparticles, we delivered exogenous miR-148b mimics to induce apoptosis in Ras-expressing keratinocytes and squamous cell carcinoma cells while causing minimal damage to normal keratinocytes both in vitro and in vivo. Using gold-silver-gold core-shell-shell (CSS) nanoparticles, we delivered exogenous miR-34a mimics to kill U87luc cells while avoiding damage to astrocytes. For both systems, we demonstrate precise spatiotemporal control and efficient delivery of miRNAs with minimized non-specific cell damage.