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Show 8 Alexander Burckle college of engineering Poly(amido amine) (PAMAM) dendrimers are a class of water-soluble macromolecules with defined spheri-cal geometry and functional surface chemistry that incrementally increases with dendrimer generation. The purpose of these experiments was to identify the role of surface charge on the biodistribution profiles of PAMAM dendrimers. Dendrimers (G3.5-COOH, G4-OH, G4-NH2, G6.5, G7-OH, G7-NH2) were character-ized by zeta potential, DLS (dynamic light scattering), HPLC, and size exclusion chromatography. These dendrimers were radiolabeled with 125I and administered to immunocompetent CD-1 mice at sub-toxic concentrations (~1mg/kg). Animals were sacrificed at various time points (2h, 8h), and major organs were collected and analyzed for radioactivity on a γ counter. Results show that G7-NH2 dendrimers accumulated most extensively in the liver whereas G7-OH and G6.5-COOH remained in blood circulation even after 8 hours post-administration (Figure 1). These results imply that surface charge plays a significant role in the biodistribution of these dendritic systems. G4-NH2 dendrimers, with size below the renal threshold, were administered to observe the dominant effects of charge over particle size. The significant accumulation of G4-NH2 dendrimers in the liver suggests that charge plays a specific role in hepatic uptake, dominating the renal clearance. We hypothesize that the cationic dendrimers opsonize plasma proteins to a greater extent than the carboxyl- and hydroxyl-terminated dendrimers, thus making them more prone to uptake by the mononuclear phagocyte system present in the liver. Theoretical calculations show that G4-NH2 has a surface charge density (σ) of 0.161 C/m2, and G7-NH2 has a surface charge density (σ) of 0.397 C/m2. Results indicate that there could potentially be a threshold for hepatic uptake as a function of surface charge density based on non-specific protein interactions. Ongoing experiments are aimed at determining the oral bioavailability of PAMAM dendrimers via surface modification with 14C acetic anhydride. Figure 1. Biodistribution of PAMAM dendrimers at 8 hours post sub-toxic i.v. injection in CD-1 mice. BIODISTRIBUTION OF POLY(AMIDO AMINE) DENDRIMERS AS A FUNCTION OF SIZE AND SURFACE CHARGE Alexander Burckle (Hamid Ghandehari) Department of Bioengineering University of Utah UNDERGRADUATE RESEARCH ABSTRACTS Hamid Ghandehari |
