G5G2.5 core‐shell tecto‐dendrimer specifically targets reactive glia in brain ischemia

Abstract

Secondary neuronal death is a serious stroke complication. This process is facilitated by the conversion of glial cells to the reactive pro-inflammatory phenotype that induces neurodegeneration. Therefore, regulation of glial activation is a compelling strategy to reduce brain damage after stroke. However, drugs have difficulties to access the CNS, and to specifically target glial cells. In the present work, we explored the use core-shell polyamidoamine tecto-dendrimer (G5G2.5 PAMAM) and studied its ability to target distinct populations of stroke-activated glial cells. We found that G5G2.5 tecto-dendrimer is actively engulfed by primary glial cells in a time- and dose-dependent manner showing high cellular selectivity and lysosomal localization. In addition, oxygen-glucose deprivation or lipopolysaccharides exposure in vitro and brain ischemia in vivo increase glial G5G2.5 uptake; not being incorporated by neurons or other cell types. We conclude that G5G2.5 tecto-dendrimer is a highly suitable carrier for targeted drug delivery to reactive glial cells in vitro and in vivo after brain ischemia.

Early Exposure to a High-Fat Diet Impacts on Hippocampal Plasticity: Implication of Microglia-Derived Exosome-like Extracellular Vesicles

“…De esta manera, la intervención en un tipo celular específico podría ser más relevante a la hora de plantear objetivos con un fin translacional. Empleando este tipo de enfoques, recientemente se ha reportado el uso de nanopartículas que son específicamente captadas por astrocitos reactivos en el contexto del proceso neuroinflamatorio que se dispara luego de un accidente cerebrovascular (Murta, Schilrreff, Rosciszewski, Morilla, & Ramos, 2018).…”

Preferential and Increased Uptake of Hydroxyl-Terminated PAMAM Dendrimers by Activated Microglia in Rabbit Brain Mixed Glial Culture

“…Their tree-like architecture offers many advantageous characteristics such as monodispersity, biocompatibility, multivalency, and customizable chemical properties [ 3 , 4 ]. In particular, polyamidoamine (PAMAM) dendrimers have been successfully used as drug, gene, and peptide delivery vehicles, as well as contrast agents [ 5 , 6 , 7 ].…”

Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke

“…Liposomes have been designed to carry dexamethasone, t-PA, or lycopene to diminish inflammation and oxidative stress [215], while studies with micelles loaded with SOD, catalase, curcumin, luteolin, quercetin, resveratrol, dexamethasone, nerve growth factor, or the nitric oxide radical amino-TEMPO also showed reduced levels of oxidative injuries, decreased neurological deficits and diminished BBB disruption [195,215]. Dendrimers are more often used to target the neuroinflammatory pathways [218]. Table 2 provides an overview of the studies performed and results obtained with nanoparticles in vitro and in animal models of stroke and Figure 3 illustrates schematically the action of the various nanomaterials.…”