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Analysis of Biotinylated Generation 4 Poly(amidoamine) (PAMAM) Dendrimer Distribution in the Rat Brain and Toxicity in a Cellular Model of the Blood-Brain Barrier
Department of Biological Sciences, Northern Kentucky University, SC 204, Highland Heights, KY 41099, USA
Department of Chemistry, Northern Kentucky University, SC 450, Highland Heights, KY 41099, USA
Center for Integrative Natural Science and Mathematics (CINSAM), Northern Kentucky University, FH 519, Highland Heights, KY 41099, USA
* Authors to whom correspondence should be addressed.
Received: 23 July 2013; in revised form: 3 September 2013 / Accepted: 10 September 2013 / Published: 17 September 2013
Abstract: Dendrimers are highly customizable nanopolymers with qualities that make them ideal for drug delivery. The high binding affinity of biotin/avidin provides a useful approach to fluorescently label synthesized dendrimer-conjugates in cells and tissues. In addition, biotin may facilitate delivery of dendrimers through the blood-brain barrier (BBB) via carrier-mediated endocytosis. The purpose of this research was to: (1) measure toxicity using lactate dehydrogenase (LDH) assays of generation (G)4 biotinylated and non-biotinylated poly(amidoamine) (PAMAM) dendrimers in a co-culture model of the BBB, (2) determine distribution of dendrimers in the rat brain, kidney, and liver following systemic administration of dendrimers, and (3) conduct atomic force microscopy (AFM) on rat brain sections following systemic administration of dendrimers. LDH measurements showed that biotinylated dendrimers were toxic to cell co-culture after 48 h of treatment. Distribution studies showed evidence of biotinylated and non-biotinylated PAMAM dendrimers in brain. AFM studies showed evidence of dendrimers only in brain tissue of treated rats. These results indicate that biotinylation does not decrease toxicity associated with PAMAM dendrimers and that biotinylated PAMAM dendrimers distribute in the brain. Furthermore, this article provides evidence of nanoparticles in brain tissue following systemic administration of nanoparticles supported by both fluorescence microscopy and AFM.
Keywords: dendrimers; atomic force microscopy; fluorescence microscopy; biotin; toxicity; blood brain barrier; lactate dehydrogenase assay
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Hemmer, R.; Hall, A.; Spaulding, R.; Rossow, B.; Hester, M.; Caroway, M.; Haskamp, A.; Wall, S.; Bullen, H.A.; Morris, C.; Haik, K.L. Analysis of Biotinylated Generation 4 Poly(amidoamine) (PAMAM) Dendrimer Distribution in the Rat Brain and Toxicity in a Cellular Model of the Blood-Brain Barrier. Molecules 2013, 18, 11537-11552.
Hemmer R, Hall A, Spaulding R, Rossow B, Hester M, Caroway M, Haskamp A, Wall S, Bullen HA, Morris C, Haik KL. Analysis of Biotinylated Generation 4 Poly(amidoamine) (PAMAM) Dendrimer Distribution in the Rat Brain and Toxicity in a Cellular Model of the Blood-Brain Barrier. Molecules. 2013; 18(9):11537-11552.
Hemmer, Ruth; Hall, Andrew; Spaulding, Robert; Rossow, Brett; Hester, Michael; Caroway, Megan; Haskamp, Anthony; Wall, Steven; Bullen, Heather A.; Morris, Celeste; Haik, Kristi L. 2013. "Analysis of Biotinylated Generation 4 Poly(amidoamine) (PAMAM) Dendrimer Distribution in the Rat Brain and Toxicity in a Cellular Model of the Blood-Brain Barrier." Molecules 18, no. 9: 11537-11552.