Doctor of Philosophy
Locoregional treatment is the specific delivery of therapeutics to their desired sites of action with minimized systemic adverse effects. In this approach, drug is administered through topical instillation, inhalation, intra-lesional or intra-arterial injection. Decades of experience in locoregional treatment have delivered meaningful benefits to patients with localized diseases (e.g., osteoarthritis, ocular disorders and liver cancers). However, improvements are required for this type of treatment to be more effective. For transarterial chemoembolization (TACE) therapy of hepatocellular carcinoma (HCC), the most current approaches do not allow repeat treatment as the drug delivery vehicle is not degradable. In addition, image contrast agents for visualization are administered separately, leading to uncertainty of the drug location.
In this thesis, the concept of a multifunctional ‘nano-on-micro’ delivery system was explored for enhanced TACE therapy. Magnetic hydrogels composed of poly(vinyl alcohol) (PVA) and iron oxide nanoparticles (IONPs) were prepared and shaped into microparticles using microfluidics. This system was able to deliver the anti-cancer drug, doxorubicin (DOX), with co-localized IONPs as a contrast agent to visualize drug location. Degradability of the PVA hydrogel carrier allows for repeat treatment. To enhance drug loading, we explored the use of silica nanoparticles (SiNPs) as an effective drug carrier. Loading was investigated using lysozyme as a model protein and applied to N-94, a therapeutic peptide for dry eye treatment. The results demonstrated SiNPs system could provide controlled drug release that is also degradable under simulated physiological conditions. Building on these results, silica (SiO2) was introduced to prepare PVA-SiO2-IONP microparticles. In addition to all the positive attributes of the original system, the PVA-SiO2-IONP microbeads have increased drug loading and tunable release profile.
The concept of a multifunctional ‘nano-on-micro’ delivery system demonstrated for TACE therapy can be applied to other diseases where locoregional treatment is applicable.
Summary for Lay Audience
Locoregional therapy is a treatment strategy where therapeutics are delivered to sites of the diseases via topical instillation, inhalation or injection. This approach can potentially minimize the involvements of invasive surgery and systemic side effects. Transarterial chemoembolization (TACE) is a locoregional therapy that is used in the treatment of hepatocellular carcinoma (HCC), which is commonly known as liver cancer. Microbeads are used to block tumor blood vessels and to deliver therapeutic drugs to the tumor site. Most of the beads currently used cannot be removed after the anti-cancer drug is delivered, so repeat treatment would not be possible. Also, to determine the location of the beads, imaging contrast agents have to be injected separately to the proximity of beads' delivery site. This causes uncertainty as to the exact location of the treatment site.
For TACE therapy, we developed a poly(vinyl alcohol) (PVA) hydrogel-based multifunctional delivery system containing iron oxide nanoparticles (IONPs) and silica (SiO2) particles that can deliver the drug and the image contrast agent within the same package. This allows the drug to be delivered effectively. In addition, the microparticles can be monitored via imaging more precisely. The delivery system is also degradable, which would allow repeat treatment at the same tumor site. These improvements would lead to enhanced treatment and better outcomes for the patients.
The concept of a multifunctional delivery system demonstrated for TACE therapy can be applied to other diseases where locoregional treatment is applicable.
Li, Xinyi, "Development of Multifunctional Drug Delivery Systems for Locoregional Therapy" (2021). Electronic Thesis and Dissertation Repository. 7944.
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