UTILIZATION OF NANOPARTICLES FOR SPECIFIC TARGETING OF ACTIVATED GLIAL CELLS

MURTA VERONICA; SCHILRREFF PRISCILA ; SEIB MARIANA; MARÍA JOSÉ MORRILLA; ALBERTO JAVIER RAMOS

Congreso; SAIC.SAI.SAFE 2016; 2016

An unequivocal association between neurodegeneration and exacerbated immune activation has arisen for most central nervous system (CNS) disorders, and the conversion of glial cells into the proinflammatory phenotype is associated with increased neuronal death. Therefore, regulation of glial activation seems a suitable strategy to reduce CNS damage in different scenarios, including brain ischemia. Unfortunately, this therapeutic strategy is challenging due to the difficulties for some drugs to access the CNS, and possible neurotoxic effect as a result of undesired impact on neurons and other cell types. Given that somepolyamidoamine (PAMAM) dendrimers were shown to be incorporated specifically byglial cells, our objective was to design nanoparticles suitable for targeted drug delivery to reactive glial cell. Considering that the activation of NFkB has been associated with glial proinflammatory phenotype, we hypothesize that targeted inhibition of the NFkB pathway in activated glial cells would diminish this phenotype. In the present work we used rat primary cell cultures, a reporter (FITC) nanoparticle, and sulfasalazine (SFZ) loaded nanoparticles. We found that a new type of core-shell tectodendrimer (G5G2.5 PAMAM) is time- and dose-dependently incorporated by astrocytes and microglia. Interestingly, the exposure to oxygen and glucose deprivation (OGD), an in vitro model of ischemia, specifically increased astroglial uptake of the G5G2.5-FITC dendrimer. Moreover, hippocampal neurons co-cultured with glia did not incorporate it. However, when analyzing the effect of the SFZ-loaded tectodendrimer,we encountered an up-regulation of the NFkB pathway, which was not compensated by the drug. In conclusion, even though the G5G2.5 showed a marked preference for activated astroglia and microglia, making it suitable as a specific drug carrier for reactive glial cells, its action on the NFkB pathway would make it unsuitable for preventing proinflammatory glial phenotype.