Date of Award

12-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Chair/Advisor

Angela Alexander-Bryant

Committee Member

Jessica Larsen

Committee Member

Brian Booth

Committee Member

Andrew Jakymiw

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, with a five-year survival rate of 6.9%. Treatment options remain challenging due to biological barriers, tumor resistance, and limited therapeutic efficacy at the tumor site. Combination therapies offer a promising approach, particularly chemotherapeutic agents like temozolomide (TMZ) and gene-silencing strategies such as small interfering RNA (siRNA). TMZ is a hydrophobic prodrug that relies on a basic pH to convert into its active form rapidly. While TMZ is the current standard of care, its efficacy is hindered by systemic delivery challenges and reduced activation in the acidic tumor microenvironment. siRNA treatment can silence oncogenes and inhibit translation into proteins in a sequence-specific manner. However, delivery is limited by poor stability and inefficient tumor targeting. Efficient drug delivery systems are needed to improve clinical applications of combination treatment strategies for GBM.

This work focuses on developing peptide-based biomaterials to improve the delivery and efficacy of therapies for GBM. Specifically, we engineered a multifunctional tandem peptide nanoparticle system for siRNA delivery. The tandem peptide incorporates both targeting and fusogenic sequences, enabling selective uptake by GBM cells and promoting endosomal escape. This system effectively complexes siRNA, protects it from degradation, and promotes oncogene silencing through improved cellular uptake and intracellular trafficking. Building on this system, we integrated the tandem-siRNA nanoparticles into cationic self-assembling peptide (CASP) hydrogels previously developed in our lab. These hydrogels are designed for local cargo delivery and are biocompatible, injectable, and utilize their degradation byproducts to serve as a local stimulus to promote TMZ conversion and bioactivity. Therefore, we leverage their use as a combination treatment platform for TMZ and tandem-siRNA nanoparticles. Characterization studies show successful loading and long-term release profiles of both cargoes from the hydrogels over 30 days, facilitating cargoes to retain bioactivity with TMZ conversion and siRNA remained protected from degradation. Synergy assays demonstrated reduced viability with TMZ and tandem-mediated gene silencing, highlighting the potential of our combination treatment strategy. Additionally, three-dimensional GBM spheroid models were characterized to better mimic tumor microenvironments, supporting their use in evaluating novel therapeutics. Collectively, this work addresses key treatment efficacy issues in GBM through engineering a peptide-based delivery platform for advancing combination therapies in GBM and improving translational outcomes through developing physiologically relevant models.

Author ORCID Identifier

0000-0003-3450-3266

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