ORCID

0009-0009-4685-2229

Keywords

Glioblastoma, stemness genes, cancer stem cell, RNAi, exosomes, brain-homing peptide, drug delivery system

Abstract

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor characterized by therapy-resistant cancer stem cells (CSCs). Due to the limited effectiveness of conventional chemotherapies and radiation treatments against cancer stem cells (CSCs), there is a critical need for the development of innovative therapeutic approaches. Our previous research revealed the significant expression of embryonic stemness genes, NANOG and OCT4, in CSCs, suggesting their role in enhancing cancer-specific stemness and drug resistance. By suppressing the expression of these genes, we observed increased susceptibility of CSCs to the anticancer drug, Temozolomide (TMZ). Furthermore, suppression of NANOG expression led to an accumulation of CSCs in the cell cycle arrest phase (G0) and a decrease in PDK1 expression. Since PDK1 activates the PI3K/AKT pathway to promote cell proliferation and survival, our findings suggest that NANOG contributes to chemotherapy resistance in CSCs through PI3K/AKT pathway activation. Therefore, the combination of Temozolomide (TMZ) treatment with RNA interference (RNAi) targeting NANOG holds promise as a therapeutic strategy for glioblastoma multiforme (GBM). However, there is a need to develop technology that can shuttle these RNA molecules to target cells within the body, specifically the brain. Extracellular vesicles (EVs) have shown a lot of promise in this area. Most research is focused on exosomes for diagnostic purposes, but their physiology makes them useful for therapeutic applications, particularly to distribute drugs. Using GFP as a fluorescent marker, we treated patient derived GSCs with HEK293 exosomes to measure cargo delivery efficiency. From our findings we determined that the addition of a brain homing peptide improved cargo uptake in vitro. Furthermore, these exosomes were able penetrate the blood-brain barrier (BBB) to deliver GFP to the brain of mice. This study describes a promising strategy in molecular therapeutics to treat neurological disorders.

Completion Date

2024

Semester

Fall

Committee Chair

Kiminobu Sugaya

Degree

Doctor of Philosophy (Ph.D.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Format

PDF

Identifier

DP0029709

Document Type

Thesis

Campus Location

College of Medicine

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