AbstractsBiology & Animal Science

The use of nanomaterials in biomedical applications has soared over the past two decades and continues to grow at a considerable pace. Nanomaterials have found clinical use in the delivery of poorly bioavailable drugs such as anti-cancer medications or anti-viral agents and have been exploited in imaging applications such as contrast agents for magnetic resonance imaging. Dendrimers and miktoarms are hyperbranched polymers that compose a unique family of nanomaterials. Their shape, size, terminal groups and lipophilicity are tunable and can be modified to contain therapeutic drugs or fluorescent tags with different targeting, loading and imaging capabilities. Further, dendrimers and miktoarms can self-assemble into micelles that have the ability to release high drug loads in biological systems. Our group has investigated the ability of low generation dendrimers with hydroxyl terminal ends to act as anti-inflammatory agents without additional drug loading. The results show that low generation dendrimers on their own can normalize biochemical and functional markers in activated immune cells such as N9 microglia. Lipopolysaccharides (LPS) from E. Coli are effective microglial activators. LPS induce nitric oxide (NO) release, cyclooxigenase-2 (COX-2) activation, changes in mitochondrial metabolic activity, and upregulation in the size and number of anti-inflammatory organelles, namely lipid droplets (LDs). Measurements of these biomarkers in our studies showed: (1) NO release was decreased by up to 70 percent upon treatment with dendrimers, while prostaglandin concentration was reduced by up to 40 percent without any significant effects to microglial health, as assessed by mitochondrial activity. (2) COX-2 activity was decreased by dendrimers, as measured by changes in PGE2 concentrations compared to LPS treated control by 45.2 to 54.3 percent. (3) Anti-inflammatory dendrimers significantly reduce the size and number of LDs in LPS-activated microglia.In order to study the use of nanoparticles as drug delivery vehicles, miktoarms were directly coupled to the anti-inflammatory drug acetaminophen. However, covalent bonding inhibited bioavailability of this small molecule drug. As such, miktoarm-derived micelles were used in subsequent experiments. These micelles were loaded with curcumin, a pleiotropic molecule with anti-inflammatory properties. Compared to free curcumin, curcumin-loaded micelles were as effective in inhibiting the release of nitric oxide from LPS-activated macrophages (IC50 10 µM). Finally, dendritic constructs were functionalized with fluorescent dyes to aid in the visualization of the internalized particles. Micelles were tagged with the fluorescent dye tetraiodofluorescein (TIF) and were visualized in cells within minutes. Dendrimers were modified with the lipophilic fluorescent dye Bodipy 493/503. This moiety allowed targeting to lipid droplets as demonstrated by co-localization with LD targeting dyes. LD-localizing dendrimers offer a platform for organelle-targeted drug delivery. Collectively, our…