| Summary: | 碩士 === 長庚大學 === 中醫學系天然藥物 === 98 === Apomorphine is a dopamine receptor agonist for treating Parkinson’s disease. However, its inherent instability, negligible oral bioavailability, and short half-life (~41 min) have complicated its applicability in clinical practice. Apomorphine was used as a model drug and encapsulated into lipid nanoparticles to enhance transport of apomomorphine into the brain in this study. Drug delivery to the central nervous system (CNS) poses a formidable challenge. Blood-brain-barrier (BBB) and blood-cerebrospinal fluid barrier can hamper effective transport of drugs into the brain. For developing a brain-specific drug carrier, we designed novel solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) to prepare drug carriers. The physicochemical properties of obtained nanoparticles were investigated and compared with lipid emulsions (LE). Lipid nanoparticles showed a size of 280~440 nm and surface charge of > 30 mV. The base form of apomorphine could be successfully entrapped by lipid nanoparticles with an entrapment percentage of 50~70%. The loading of apomorphine in lipids nanoparticles resulted in slower release behavior as compared to the aqueous solution. CN5, a modified NLC by incorporating cationic emulsifiers, polysorbate 80, and polyethylene glycol (PEG), was prepared to investigate whether the duration and accumulation of apomorphine in brain can be improved by intravenous delivery. In vivo real-time fluorescence imaging in rat brain revealed that CN5 was targeted through vessels to the brain. This effect was further confirmed by imaging the whole brain and brain slices. The results indicate that NLC with moderate additives are a promising controlled release and brain targeting system. In the second part, we designed drug carriers for helping drugs cross BBB. The particle size of lipid nanoparticles was 200 nm, and the zeta potential was > 40 mV. We chose sulforhodamine B to labeled lipid nanoparticles. In vitro study revealed that F1 and F3 were uptaked into bEND3, a mouse brain derived endothelial cells, and by energy-dependent caveolae and macropinocytosis pathways. In in vivo study, we further confirmed that F1 and F3 displayed a prolonged retention of sulforhodamine B in rat brain.
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