Date of Award
12-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemical and Biomolecular Engineering
Committee Chair/Advisor
Jessica Larsen
Committee Member
Scott Husson
Committee Member
Marc Birtwistle
Committee Member
Heather Dunn
Abstract
Glioblastoma (GBM) accounts for over 66% of all malignant central nervous system and brain tumors with a 5-year survival rate below 5%, which has remained relatively unchanged over the last four decades. To bypass the most challenging barrier to treatment, the blood-brain barrier (BBB), one intracranial implant is clinically available for GBM treatment. However, this treatment produces severe adverse effects with no significant improvements in patient outcomes. Developing an improved delivery system with a more effective chemotherapy drug will provide more controlled and specific treatment through local delivery. In this dissertation, I evaluate a hyaluronic acid-b-polylactic acid (HA-PLA) polymersome system as a delivery vehicle, releasing doxorubicin (DOX) at the tumor site through pH-triggered release. DOX is proven to effectively inhibit GBM growth through inhibition of the topoisomerase (TOPO) II enzyme during DNA synthesis, with high clinical translatability when administered locally. The slightly acidic tumor microenvironment (TME) and cluster of differentiation 44 (CD44) overexpression in GBM provide increased specificity and controlled release from HA-PLA polymersomes. Both HA and PLA undergo acidic hydrolytic degradation, causing higher drug release within the TME, while CD44 has an inherent affinity for binding to HA.
HA-PLA polymersomes were self-assembled via the solvent-injection method. With an average diameter of 101.8 ± 16.5 nm and ζ-potential of -11.3 ± 1.5 mV, HA-PLA polymersomes were able to encapsulate DOX with 98 ± 2%. A 2.96- and 1.18-fold increase in the drug release rate for 6 and 24 μg DOX/mL dosages, respectively, was observed in acidic conditions. Gel electrophoresis qualified DOX-induced TOPO II inhibition. Verification of cellular uptake and CD44-HA binding was performed with polymersomes loaded with fluorescein isothiocyanate (FITC)-tagged bovine serum albumin (BSA) for flow cytometry analysis. The addition of free HA is suspected to bind the available CD44 receptors in competition with the polymersomes, shown by a 50% reduction in the normalized mean fluorescent intensity in the competitive environment compared to the non-competitive environment. The studies in my dissertation demonstrate that HA-PLA polymersomes can potentially deliver DOX at higher rates in the GBM TME through pH-triggered degradation and increased specificity through HA-CD44 binding, providing an improved delivery system to treat GBM.
Recommended Citation
Garifo, Molli, "Polymersomes As Chemotherapeutic Agents Towards Non-Invasive Treatment Of Glioblastoma" (2024). All Dissertations. 3831.
https://open.clemson.edu/all_dissertations/3831
Author ORCID Identifier
0000-0003-0414-3108
