Akademik Veri Yönetim Sistemi
Tezin Türü: Yüksek Lisans
Tezin Yürütüldüğü Kurum: Orta Doğu Teknik Üniversitesi, Mühendislik Fakültesi, Mühendislik Bilimleri Bölümü, Türkiye
Tezin Onay Tarihi: 2014
Öğrenci: ZEYNEP BARÇİN
Danışman: DİLEK KESKİN
Özet:Localized and controlled delivery of drugs at their site of action is necessary to increase its efficiency. Current study was designed on the development of a brain targeted liposomal Levodopa delivery system for the treatment of the Parkinson’s disease. Size and surface charge of the liposomes were modified and optimized to increase the bioavailability and effectiveness of the liposomes. The liposomes were produced in sizes to be administrated intravenously (D: 100-150 nm). In initial optimization studies, the conventional Large Unilamellar Vesicles (LUVs) were prepared with three different molar lipid compositions (DPPC:Cho; 8:2, 7:3, and 6:4) at four different temperatures (38, 40, 42 and 44oC). Among the conventional LUVs, DPPC:Cho (7:3) liposomes prepared at 40oC with the highest Levodopa encapsulation efficiency and slowest cumulative Levodopa release was PEGylated with two different ratios (2 and 4 mole percentage of DPPC). PEGylated liposomes (i.e. 2% PEG/LUV and 4% PEG/LUV) had slower in vitro cumulative percent Levodopa release than conventional liposomal formulations. The targeted liposomes were prepared with two different mole percentage of maltodextrin (i.e. 0.35 and 0.7 mole percentage of DPPC) conjugation to 4% PEG/LUV (i.e. 0.35% MD-4% PEG/LUV and 0.7% MD-4% PEG/LUV). Maltodextrin conjugated liposomes are promising for brain drug delivery via receptor-mediated endocytosis. This study is novel for developing maltodextrin conjugated liposomes as a brain targeted delivery system for the first time. Later, the targeted liposomal formulation 0.7% MD-4% vi PEG/LUV was loaded with both Levodopa and GSH (LD-20μM GSH-0.7% MD-4% PEG/LUV and LD-40μM GSH-0.7% MD-4% PEG/LUV). The antioxidant GSH was incorporated to improve liposome stability and drug bioavailability. This study is also new for bringing Levodopa and GSH in the same liposomal formulation. Among all experimental groups, LD-40μM GSH-0.7% MD-4% PEG/LUV had the slowest in vitro cumulative percent Levodopa release (19.12 ± 0.97% and 31.07 ± 1.98% at 24 and 48 hours, respectively). In vitro cytotoxicity experiments revealed that percent viabilities of the 3T3 and SH-SY5Y cells were higher than 80% after 48 hours incubation with liposomal formulations. Among experimental groups, LD-40μM GSH-0.7% MD-4% PEG/LUV had the highest Levodopa passage in Parallel Artificial Membrane Permeability Assay for Blood-Brain Barrier (PAMPA-BBB) and had superior binding to MDCK cells via receptor mediated association. LD-40μM GSH-0.7% MD-4% PEG/LUV was found quite stable at 4oC after 5 months with good particle size distribution and drug encapsulation efficiency. These data suggest that designed dual loaded maltodextrin conjugated liposomal formulation is promising in brain targeted drug delivery with controlled and sustained drug release property, low cellular cytotoxicity, good BBB delivery, and good stability. This brain targeted liposomal delivery system will bring a novel approach for the delivery of Levodopa to increase brain transition with decreased drug side effects.