UTILIZATION OF NANOPARTICLES FOR SPECIFIC TARGETING OF ACTIVATED GLIAL CELLS

MURTA V; SCHILRREFF P; SEIB M; MORRILLA MJ; RAMOS AJ

Mar del Plata

Congreso; LXI meeting de la Sociedad Argentina de Investigacion Clínica (SAIC); 2016

Sociedad Argentina de Investigacion Clinica - Sociedad Argentina de Inmunología

An unequivocal association between neurodegeneration andexacerbated immune activation has arisen for most central nervoussystem (CNS) disorders, and the conversion of glial cells into theproinflammatory phenotype is associated with increased neuronaldeath. Therefore, regulation of glial activation seems a suitablestrategy to reduce CNS damage in different scenarios, includingbrain ischemia.Unfortunately, this therapeutic strategy is challengingdue to the difficulties for some drugs to access the CNS,and possible neurotoxic effect as a result of undesired impact onneurons and other cell types. Given that some polyamidoamine(PAMAM) dendrimers were shown to be incorporated specificallyby glial cells, our objective was to design nanoparticles suitablefor targeted drug delivery to reactive glial cell.Considering that the activation of NFkB has been associatedwith glial proinflammatoryphenotype, we hypothesize thattargeted inhibition of the NFkB pathway in activated glial cellswould diminish this phenotype. In the present work we used rat primary cell cultures, a reporter (FITC) nanoparticle, andsulfasalazine (SFZ) loaded nanoparticles. We found that a newtype of core-shell tectodendrimer (G5G2.5 PAMAM) is time- anddose-dependently incorporated by astrocytes and microglia. Interestingly,the exposure to oxygen and glucose deprivation (OGD),an in vitro model of ischemia, specifically increased astroglialuptake of the G5G2.5-FITC dendrimer. Moreover, hippocampalneurons co-cultured with glia did not incorporate it. However,when analyzing the effect of the SFZ-loaded tectodendrimer, weencountered an up-regulation of the NFkB pathway, which wasnot compensated by the drug. In conclusion, even though theG5G2.5 showed a marked preference for activated astroglia andmicroglia, making it suitable as a specific drug carrier for reactiveglial cells, its action on the NFkB pathway would make it unsuitablefor preventing proinflammatory glial phenotype.