Publicação
BLOOD BRAIN BARRIER (BBB) PERMEABILITY STUDIES OF NOVEL LIPID NANOPARTICLES (LNPS) FOR THE DELIVERY OF PROMISING DRUGS IN ALZHEIMER DISEASE
| Resumo: | Dementia is one of the most common events associated with brain aging, estimated to reach 139 million people in 2050, with Alzheimer's disease (AD) being its most prevalent form. The blood brain barrier (BBB) acts as a wall for blood circulating substances and blocking 98% of brain-targeted drugs. Solid lipid nanoparticles (SLNPs) have shown promising potential as therapy vehicles for neurological disorders. They are commonly composed of a solid lipidic core surrounded by a surfactant layer, provid- ing an efficient biocompatible carrier to transport therapeutic agents through BBB. The aim of this work consists of characterizing a novel SLNP formulation, assessing their potential as delivery systems for AD therapy. SLNPs, supplied by external collaborators, were incubated for different periods at room temper- ature and 37 ºC, in ultrapure water and endothelial basal medium, mimicking in vitro conditions, and physico-chemically characterized. These presented high size stability (103.69 ± 3.18 nm and 56.39 ± 0.78, for batch#1 and #2 respectively) throughout the incubation periods in both solvents. A slight size increase was reported as consequence of cluster formation due to the increase in temperature, allowing for the lipidic particles to get closer together, with transmission electron microscopy confirming these results. Cytotoxicity of SLNPs on human brain microvascular endothelial cells was assessed and cell uptake capacity by flow cytometry and confocal microscopy. These show signs of harmful behavior towards cells, indicating a possible problem with the formulation. A lack of internalization of lower, non-toxic, concentrations of SLNPs was also reported. The individual components were assessed, iden- tifying Brij S20 as the root of the toxicity issue. This work proposes the complete removal of this surfactant from the formulation, its decrease in concentration to 0.05% (w/v) of the final formulation or the development of a purification process of the system, drawing out the true potential of the SLNPs. |
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| Autores principais: | Gil, Alexandre Descalço |
| Assunto: | Alzheimer's Disease Blood Brain Barrier Cytotoxicity Precirol® ATO5 Solid Lipid Nanoparticles Surfactants |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Dementia is one of the most common events associated with brain aging, estimated to reach 139 million people in 2050, with Alzheimer's disease (AD) being its most prevalent form. The blood brain barrier (BBB) acts as a wall for blood circulating substances and blocking 98% of brain-targeted drugs. Solid lipid nanoparticles (SLNPs) have shown promising potential as therapy vehicles for neurological disorders. They are commonly composed of a solid lipidic core surrounded by a surfactant layer, provid- ing an efficient biocompatible carrier to transport therapeutic agents through BBB. The aim of this work consists of characterizing a novel SLNP formulation, assessing their potential as delivery systems for AD therapy. SLNPs, supplied by external collaborators, were incubated for different periods at room temper- ature and 37 ºC, in ultrapure water and endothelial basal medium, mimicking in vitro conditions, and physico-chemically characterized. These presented high size stability (103.69 ± 3.18 nm and 56.39 ± 0.78, for batch#1 and #2 respectively) throughout the incubation periods in both solvents. A slight size increase was reported as consequence of cluster formation due to the increase in temperature, allowing for the lipidic particles to get closer together, with transmission electron microscopy confirming these results. Cytotoxicity of SLNPs on human brain microvascular endothelial cells was assessed and cell uptake capacity by flow cytometry and confocal microscopy. These show signs of harmful behavior towards cells, indicating a possible problem with the formulation. A lack of internalization of lower, non-toxic, concentrations of SLNPs was also reported. The individual components were assessed, iden- tifying Brij S20 as the root of the toxicity issue. This work proposes the complete removal of this surfactant from the formulation, its decrease in concentration to 0.05% (w/v) of the final formulation or the development of a purification process of the system, drawing out the true potential of the SLNPs. |
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