Locally Injectable Peptide Hydrogel for Conversion of Temozolomide and Codelivery of siRNA in Glioblastoma Multiforme Treatment

Author

Megan PitzFollow

Date of Award

5-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Bioengineering

Committee Chair/Advisor

Angela Alexander-Bryant

Committee Member

Robert Latour

Committee Member

Brian Booth

Committee Member

Jessica Larsen

Abstract

Traditional treatment methods for glioblastoma multiforme (GBM) are largely unsuccessful, with a 5-year survival rate of 5.6%. Temozolomide (TMZ), the only chemotherapy FDA-approved for GBM treatment, is a hydrophobic prodrug that is stable in an acidic pH and begins converting to its active form at a physiological pH of 7.4. However, complete conversion of TMZ is observed only at a higher pH, and only about 30% of administered TMZ reaches the central nervous system. Therefore, there is a need for new treatment methods that maximize TMZ delivery to and efficacy at the tumor site. Self-assembling peptides are a unique class of biomaterials that spontaneously assemble to create a wide array of supramolecular structures. Because they are tunable and biodegradable, peptide materials have been explored for in vivo applications such as drug delivery and tissue engineering.

This work explores de novo and established self-assembling peptide drug delivery systems as delivery vehicles that can induce TMZ conversion upon delivery. Because many GBM tumors exhibit drug resistance to TMZ alone, we codeliver TMZ with an additional peptide-siRNA nanoparticle complex to induce oncogene silencing. Our results show that de novo self-assembled peptide hydrogels can be tuned to trigger the conversion of TMZ upon degradation and release. Additionally, established cationic peptide hydrogels were repurposed, utilized for TMZ delivery, and found to effectively convert TMZ upon degradation. Peptide hydrogels were characterized and found to be locally injectable, self-healing, and biocompatible. Finally, self-assembled peptide hydrogels were evaluated for anticancer efficacy in 2D and 3D in vitro GBM models. We found that our hydrogels mediate cellular internalization of multiple cargoes, resulting in cancer cell death. This work demonstrates that peptide-based drug delivery systems can effectively create a local stimulus during drug delivery while retaining drug delivery functionality. This principle could be used in many future biomedical applications in addition to cancer treatment, such as wound healing and regenerative medicine.

Recommended Citation

Pitz, Megan, "Locally Injectable Peptide Hydrogel for Conversion of Temozolomide and Codelivery of siRNA in Glioblastoma Multiforme Treatment" (2024). All Dissertations. 3554.
https://open.clemson.edu/all_dissertations/3554