Date of Award

8-2018

Document Type

Thesis

Degree Name

Master of Science (MS)

Department

Bioengineering

Committee Member

Angela Alexander-Bryant, Ph.D., Committee Chair

Committee Member

Jessica Kelly, Ph.D.

Committee Member

Robert Latour, Ph.D.

Abstract

Gliomas represent approximately 80% of all malignant brain tumors, and glioblastoma multiforme (GBM) accounts for nearly half of all gliomas. GBM is the most common and aggressive primary brain tumor. Despite aggressive treatment including tumor resection followed by radiation and chemotherapy, the median survival rate for GBM averages between 12 and 15 months, with a 2-year survival rate less than 25%. Therefore, new therapeutic strategies are needed to improve the survival rate of those affected by GBM. Chemotherapy with the DNA alkylating agent, Temozolomide (TMZ), is commonly used as a first-line treatment for GBM. TMZ is an orally delivered drug that is known to be stable or inactive in the acidic pH environment of the stomach and begins to convert to its active form at a neutral pH in the bloodstream. However, studies have shown that full conversion of TMZ to its active form occurs at a more basic pH. Further, after TMZ is converted to its active form, it is unable to cross the blood-brain barrier, thereby limiting availability in the brain and lowering the effectiveness of TMZ. Recently, peptides have been utilized as delivery systems for hydrophobic anticancer drugs or agents. These peptides are advantageous due to their biocompatibility, and high loading capacity for hydrophilic and hydrophobic drugs. To facilitate the delivery of TMZ, and potentially other hydrophobic drugs, we propose an innovative local delivery strategy using hydrophilic and alternating hydrophobic and acidic amino acids to form a peptide hydrogel. We hypothesize that the hydrophobic residues of the peptide hydrogel will load TMZ, and the hydrophilic residues will convert TMZ to its active form as the hydrogel degrades. This therapeutic strategy will allow for extended release of TMZ, thus increasing the efficacy of the drug. In this study, peptide sequences were designed, synthesized, and formed into hydrogels for the delivery of TMZ. In vitro experiments validated that TMZ dissolved at a higher pH resulted in significantly increased cytotoxicity in LN-18 and T98G human glioblastoma cells. We also demonstrated that at various concentrations, the proposed peptide hydrogel efficiently loads TMZ and the release profiles can be adjusted based on peptide composition. Further, studies showed that TMZ-loaded peptide hydrogels mediated greater anticancer activity in LN-18 cells compared to delivery of TMZ alone. Overall, our results demonstrate the therapeutic potential of the TMZ-loaded peptide hydrogels for local drug delivery in treating GBM.

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