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Molecules 2018, 23(5), 1025; https://doi.org/10.3390/molecules23051025

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

1
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2
Center for Nanomedicine, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins, University School of Medicine, Baltimore, MD 21205, USA
3
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Co-first authors, the authors contributed equally to this work.
Current Address: Department of Pediatrics, BC Children’s Hospital, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
§
Current Address: Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USA.
*
Authors to whom correspondence should be addressed.
Received: 20 March 2018 / Revised: 18 April 2018 / Accepted: 20 April 2018 / Published: 27 April 2018
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Abstract

Polyamidoamine (PAMAM) dendrimers are multifunctional nanoparticles with tunable physicochemical features, making them promising candidates for targeted drug delivery in the central nervous system (CNS). Systemically administered dendrimers have been shown to localize in activated glial cells, which mediate neuroinflammation in the CNS. These dendrimers delivered drugs specifically to activated microglia, producing significant neurological improvements in multiple brain injury models, including in a neonatal rabbit model of cerebral palsy. To gain further insight into the mechanism of dendrimer cell uptake, we utilized an in vitro model of primary glial cells isolated from newborn rabbits to assess the differences in hydroxyl-terminated generation 4 PAMAM dendrimer (D4-OH) uptake by activated and non-activated glial cells. We used fluorescently-labelled D4-OH (D-Cy5) as a tool for investigating the mechanism of dendrimer uptake. D4-OH PAMAM dendrimer uptake was determined by fluorescence quantification using confocal microscopy and flow cytometry. Our results indicate that although microglial cells in the mixed cell population demonstrate early uptake of dendrimers in this in vitro system, activated microglia take up more dendrimer compared to resting microglia. Astrocytes showed delayed and limited uptake. We also illustrated the differences in mechanism of uptake between resting and activated microglia using different pathway inhibitors. Both resting and activated microglia primarily employed endocytotic pathways, which are enhanced in activated microglial cells. Additionally, we demonstrated that hydroxyl terminated dendrimers are taken up by primary microglia using other mechanisms including pinocytosis, caveolae, and aquaporin channels for dendrimer uptake. View Full-Text
Keywords: PAMAM hydroxyl dendrimers; activated microglia; mixed primary glial cultures; intracellular trafficking; enhanced cellular uptake; neuroinflammation PAMAM hydroxyl dendrimers; activated microglia; mixed primary glial cultures; intracellular trafficking; enhanced cellular uptake; neuroinflammation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Alnasser, Y.; Kambhampati, S.P.; Nance, E.; Rajbhandari, L.; Shrestha, S.; Venkatesan, A.; Kannan, R.M.; Kannan, S. Preferential and Increased Uptake of Hydroxyl-Terminated PAMAM Dendrimers by Activated Microglia in Rabbit Brain Mixed Glial Culture. Molecules 2018, 23, 1025.

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