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.
Highlights
In recent years, the field of nanotechnology has emerged as an important area of biomedical research
G4 PAMAM dendrimers were conjugated to biotin prior to evaluation of toxicity
Because biotin is found throughout the body, we hypothesize that dendrimers functionalized with biotin would be non-toxic
Summary
The field of nanotechnology has emerged as an important area of biomedical research. [1,2,3,4] While this disease model has shown promise for the use of NPs and nanocarrier drug delivery systems, the issues of biodistribution and toxicity need to be addressed. The nanosize dimensions of NPs have been reported to facilitate the crossing of several biological barriers such as the skin, tight junctions of various epithelial layers, and the blood-brain barrier (BBB) [5,6]. The walls of BBB capillaries are composed of brain capillary endothelial cells (BCEC), which form tight junctions. Tight junctions contain integral membrane proteins that form a seal between adjacent endothelial cells. The poor permeability of various drugs and delivery systems across the BBB is primarily due to tight junctions, lack of capillary fenestrations and presence of efflux transporters. Finding new ways to deliver therapeutic drugs to the CNS safely and effectively is essential
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