2024-03-28T14:07:14Zhttps://www.tdx.cat/oai/requestoai:www.tdx.cat:10803/4580262018-09-21T02:00:10Zcom_10803_1col_10803_400197
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Malaltia d'Alzheimer
Enfermedad de Alzheimer
Alzheimer's disease
Nanopartícules
Nanopartículas
Nanoparticles
Glaucoma
Nanostructured systems for therapeutic treatment of neurodegenerative diseases = Sistemas nanoestructurados en el abordaje terapéutico de enfermedades neurodegenerativas
[Barcelona] :
Universitat de Barcelona,
2017
Accés lliure
http://hdl.handle.net/10803/458026
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Sánchez-López, E. ,
(Elena)
autor
1 recurs en línia (186 pàgines)
Tesi
Doctorat
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
2017
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
Tesis i dissertacions electròniques
García López, María Luisa,
supervisor acadèmic
Egea Gras, Ma. Antonia,
supervisor acadèmic
García López, María Luisa,
supervisor acadèmic
TDX
The incidence of neurodegenerative diseases, such as Alzheimer's disease, increases every year due to population aging. Therefore, the development of new therapeutic strategies, such as biodegradable nanostructured systems like poly-lactic-co-glycolic acid functionalized with polyethylene glycol (PLGA-PEG) is extremely necessary in order to provide greater therapeutic adherence as well as to reduce the adverse effects of the drugs. Glaucoma is currently considered a neurodegenerative disease since there is a direct connection between the brain and the last ocular structures sharing many characteristic features with Alzheimer's disease. The only drug approved for moderate to severe phases of Alzheimer's is Memantine Hydrochloride (MEM). Clinical studies with Ibuprofen have shown that the levels of markers associated with the disease decrease with this drug. Therefore, the main objective of this thesis is the development and characterization of PLGA-PEG nanostructured systems encapsulating MEM drugs and Dexibuprofen (DXI, active enantiomer of ibuprofen) in order to increase the passage through the blood-brain barrier (BBB) and hematoretinal barrier (BHR).
The developed nanostructured systems were optimized in order to obtain homogeneous nanoparticles with an average size below 200 nm with a high encapsulation efficiency (80-99%). These systems were characterized by spectroscopic methods (X-ray diffraction or infrared spectroscopy) and thermal methods (differential scanning calorimetry), confirming the correct incorporation of the drug into the particles without the formation of new covalent bonds. The in vitro release profile of these systems showed a sustained release, more prolonged than the free drug with two phases (an initial rapid phase due to the drug attached to the surface followed by a slower release of the encapsulated drug). The corneal and scleral permeation of the systems showed a tropism of the nanoparticles towards the corneal tissues. In vitro studies confirmed that the nanoparticles developed were neither cytotoxic in brain nor retinal cells and that they are able cross trough the BBB. Although free MEM did affect cell viability by acting the nanoparticles as protection.
The systems developed were tested in vivo for Alzheimer's disease, glaucoma and ocular inflammation. The experiments regarding Alzheimer's disease, were carried out using a double transgenic mouse model and by administering the nanoparticles orally. It was shown that both MEM and DXI nanoparticles decreased the level of β-amyloid plaques and the associated inflammatory brain process. The results of MEM nanoparticles assessed for glaucoma disease in rats using the ocular hypertension model by administering two drops per day of these systems demonstrated that, despite not decreasing intraocular tension, the systems prevent the death of the retinal ganglion cells. In addition, ocular administration of DXI nanoparticles demonstrated to be more effective in preventing ocular inflammation than the free drug, for these reason it would be indicated in the prophylaxis of inflammation secondary to ocular surgery.
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