Development of Multifunctional Drug Delivery Systems for Locoregional Therapy

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 ...