Soft biomaterials for applicatons as local drug delivery systems for use in the brain

Wang, Yu 2025. Soft biomaterials for applicatons as local drug delivery systems for use in the brain. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Glioblastoma is the most malignant brain tumour with less than two years median survival time after the first diagnosis. The current treatment strategy is based on the Stupp protocol established in 2005, which consists of surgery, radiotherapy, and temozolomide. The choice of chemotherapeutics is limited to lipophilic alkylating agents due to their ability to pass the blood-brain barrier. However, temozolomide might only have activity in O6-methylguanine-DNA methyltransferase (MGMT) promoter-methylated tumours. So, glioblastoma is an unmet medical need, and it is urgent to develop effective, safe, and long-lasting treatment approaches. Drug repurposing is a strategy that repositions existing drugs for new medications, stimulating drug discovery by reducing drug development time and investment. This strategy also avoids the chemoresistance of glioblastoma to alkylating agents. Tumour recurrence is another intractable issue for glioblastoma treatment, and the standard of care has not been well defined. However, most recurrences occur close to the margin of surgery or radiotherapy, providing a critical rationale for local treatment. Local drug delivery could also bypass the blood-brain barrier, reach higher drug concentrations, and reduce systemic adverse effects. In this project, I focus on the local treatment strategies against glioblastoma and commit to resolving the key problems including mechanical properties of the materials, chemoresistance, and sustained long-term drug release. First, publications about injectable drug delivery systems for glioblastoma local treatment were systematically searched. The meta-analysis results of these preclinical studies showed that injectable drug delivery devices improved efficacy compared to systemic or local administration of free drugs. The first objective of this project was to create cylindrical-shaped cryogels as an implant to deliver clemastine to a mouse glioblastoma resection model. The mechanical properties of this spongy-like cryogel approximately matched the soft brain tissue. Cryogels showed good in vitro cytocompatibility and in vivo biocompatibility. However, the variability in the extent of surgical resection may act as a confounding factor, affecting the clemastine treatment efficacy. In the second objective, microscale cryogels, termed cryogel microcarriers, were designed to be an injectable local drug delivery system flexibly administered to tumour resection cavities with various sizes. The drug loading efficiency and drug release profiles were investigated with four model drugs, doxorubicin, venetoclax, brexpiprazole, and vortioxetine. In vitro antitumor efficacy studies were performed with brexpiprazole microcarriers due to the best in vitro drug loading efficiency and release paterns. The results showed that brexpiprazole microcarriers effectively reduced cell viability both on 2D and 3D iii cell culture models. The third objective aimed to create poly lactic-co-glycolic acid (PLGA) microsphere delivery systems to resolve the rapid release of vortioxetine microcarriers. A novel methodology was developed to create monodisperse and highly reproducible PLGA microspheres by droplet-based microfluidics. Vortioxetine microspheres achieved one month of sustained drug release without burst release. Empty PLGA microspheres had good cytocompatibility on primary human astrocytes, suggesting the water-free emulsion system did not introduce any toxic reagents into the final product. Vortioxetine microspheres reduced glioblastoma cell viability in a dose-dependent and time-dependent manner. In summary, I developed cylindrical cryogel, cryogel microcarriers, and PLGA microspheres as local drug delivery systems for glioblastoma treatment. Repurposed drugs, clemastine, brexpiprazole, and vortioxetine showed a therapeutic window that effectively killed the tumour cells while being safe for astrocytes. Together strategies of novel local drug delivery systems and repurposed drugs provide promising approaches against glioblastoma.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Pharmacy
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	7 July 2025
Last Modified:	07 Jul 2025 16:08
URI:	https://orca.cardiff.ac.uk/id/eprint/179574

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