Nanoparticles Targeting at Inflammation Site

This thesis presents the development and translational evaluation of advanced nanoparticle-based drug delivery systems designed for the sustained and localized delivery of hydrophobic therapeutics, with a focus on pazopanib. Addressing key challenges in drug solubility, stability, and scalable manufacturing, this work explores polymeric, lipid-based, and peptide-modified nanocarriers tailored for chronic disease applications. In the context of osteoarthritis (OA)-associated pain, two classes of biodegradable polymeric nanoparticles—PEG-b-PCL and PLGA—were investigated for their distinct drug release kinetics. PEG-b-PCL enabled prolonged, near zero-order release, whereas PLGA exhibited a rapid burst release. These insights informed the development of a clinically translatable formulation, PEG-PCL-NanoPaz-t, produced via flash nanoprecipitation followed by spray drying. This scalable approach achieved over a 9,000-fold increase in production rate and maintained the therapeutic efficacy of pazopanib in a canine OA model, demonstrating extended pain relief and improved drug solubility. In parallel, the formulation and stability of lipid nanoparticles (LNPs) were enhanced through rational surface engineering. A comparative study between conventional PEG-lipids and zwitterionic peptide–lipid conjugates revealed that C(EK)₄-modified LNPs significantly improved membrane integrity and reduced enzymatic degradation, as demonstrated by synchrotron-based X-ray scattering. These EK4-modified LNPs successfully encapsulated pazopanib and exhibited long-term colloidal stability, suggesting their potential application in targeted renal carcinoma therapy. Collectively, this work highlights how material-driven design can overcome pharmacological and manufacturing bottlenecks in nanoparticle drug delivery. The results contribute broadly to the development of robust nanocarriers for chronic disease treatment, supporting future clinical translation.