Anti-parkinsonian drug delivery across the blood-brain barrier

Download
index.pdf
2014
Barçin, Zeynep
Show full item record
329
views
117
downloads
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.
Parkinson's disease., Blood-brain barrier., Drug delivery systems., Liposomes., Glutathione.
http://etd.lib.metu.edu.tr/upload/12616900/index.pdf
https://hdl.handle.net/11511/23330
Graduate School of Natural and Applied Sciences, Thesis

Suggestions

Controlled doxorubicin delivery from photoresponsive liposomes carrying vitamin A derivatives /
Heper, Senem; Hasırcı, Vasıf Nejat; Hasırcı, Nesrin; Department of Biotechnology (2014)
Drug delivery systems (DDS) have been an attractive approach to eliminate the drawbacks of conventional drug administration. Controlled and photoresponsive drug delivery systems have a special advantage; they deliver drugs more effectively. Liposomes are mostly preferred as drug carriers due to their ability to carry both hydrophilic and hydrophobic drugs, their being non-toxic and non-immunogenic. In this study, photoresponsive liposomes were prepared by incorporating vitamin A derivatives into the lipid b...
Biopolymer based micro/nanoparticles as drug carriers for the treatment of skin diseases
Eke, Gözde; Hasırcı, Vasıf Nejat; Hasırcı, Nesrin; Department of Micro and Nanotechnology (2011)
Controlled drug delivery systems are becoming increasingly interesting with the contribution of nanotechnology. In the case of transdermal applications the greatest limitation is the highly impermeable outermost layer of the skin, the stratum corneum. One promising method of controlled transdermal drug delivery of the skin therapeutics is the use of nanoparticles as carriers. Encapsulation of the drug, as opposed to classical topical application of creams or emulsions, allows the drug to diffuse into hair f...
UV responsive drug delivery from suprofen incorporated liposomes
Demirbağ, Birsen; Hasırcı, Vasıf Nejat; Hasırcı, Nesrin; Department of Biotechnology (2011)
Drug delivery systems are designed to achieve low, local doses at the target site. Delivery systems can provide the drug in a continuous manner or in response to environmental stimuli such as temperature, pH or UV. This study aimed to develop photosensitive liposomes that achieve UV-responsive release of their content. The main mechanism was to incorporate a light sensitive molecule into the liposomal bilayer then achieve destabilization of the membrane by exposure to UV. This would result in an on demand r...
Inclusion of celecoxib in the SBA-15 mesoporous silica: drug loading and release property
Eren, Zeynep Seda; Yılmaz, Ayşen; Department of Chemistry (2016)
Mesoporous silica particles have been used to enhance the loading capacity of drugs into the support, increase the solubility of drug and control drug release. In this study, poorly water-soluble, nonsteroidal anti-inflammatory drug with relatively low bioavailability Celecoxib, was used as a model drug in order to determine the drug loading and release properties of silica particles. In order to synthesize SBA15 particles, hydrothermal synthesis method was used, SBA-15 samples were functionalized by post-g...
Antinociceptive effects of hydromorphone, bupivacaine and biphalin released from PLGA polymer after intrathecal implantation in rats
Sendil, D; Bonney, IM; Carr, DB; Lipkowski, AW; Wise, DL; Hasırcı, Vasıf Nejat (2003-05-01)
Intraspinal drug delivery, based on the concept of controlling pain by delivering drug to a nociceptive target rich in opioid and other relevant receptors is increasingly used clinically. The therapeutic ratio for opioids or other centrally acting agents is potentially greater if they are administered intrathecally (i.t.) than outside the central nervous system (CNS). The present study was designed with the ultimate goal of formulating a controlled release system for intrathecal analgesia characterized by e...
Citation Formats
Z. Barçin, “Anti-parkinsonian drug delivery across the blood-brain barrier,” M.S. - Master of Science, Middle East Technical University, 2014.
METU IIS - Integrated Information Service open@metu.edu.tr