The broad long-term goal of this research is to develop an efficient oral drug delivery system using poly amidoamine (PAMAM) dendrimers as drug carriers. Generally, a polymeric component serves as a drug carrier in controlled drug delivery systems. These systems are usually administered parenterally (eg: intravenous) because polymeric carriers exhibit low permeability across the intestinal epithelial barrier. However, oral drug delivery is the most desired route of drug administration due to high patient compliance. PAMAM has been shown to have relatively high permeability across the intestinal epithelial barrier. This research proposal will investigate the factors that influence the permeability of PAMAM. First, Confocal Scanning Laser Microscopy (CSLM) techniques will be used to investigate the transport mechanisms of amine-terminated poly amidoamine (PAMAM-NH2) dendrimers across Caco-2 cell monolayers. The testable hypothesis is that the visualization of the transport pathways of fluorescently labeled PAMAM-NH2 dendrimers will elucidate possible contribution of the paracellular and/or transcellular routes in the permeability of PAMAM-NH2 dendrimers. Elucidation of the transport pathways utilized by PAMAM dendrimers will be determined by the visualization of Caco-2 cell monolayers upon incubation with fluorescently labeled PAMAM dendrimers using CSLM techniques. Furthermore, the effect of drug loading on the permeability of PAMAM-NH2 dendrimers across Caco-2 cells will be studied. The hypothesis to be tested is that an increase in hydrophobic drug loading is expected to increase the transcellular transport of PAMAM dendrimers. The effect of hydrophobic drug loading on PAMAM permeability will be assessed by examining PAMAM permeability upon increasing the extent of FlTC labeling per PAMAM generation (G0-G4). Finally, the influence of surface charge of PAMAM dendrimers on their transepithelial transport will be investigated. The hypothesis to be tested is that both negatively charged and positively charged dendrimers will have higher permeability values than the neutral dendrimers. The permeability of neutral, hydroxyl-terminated (PAMAM-OH, G2-G4) and anionic, carboxylate-terminated dendrimers (PAMAM-COOH, G0.5-G4.5) in comparison to the permeability of cationic, amine-terminated dendrimers (PAMAM-NH2, G0-G4) will be used to assess the effect of surface charge on PAMAM permeability.
| Kitchens, Kelly M; Kolhatkar, Rohit B; Swaan, Peter W et al. (2008) Endocytosis inhibitors prevent poly(amidoamine) dendrimer internalization and permeability across Caco-2 cells. Mol Pharm 5:364-9 |
| Kolhatkar, Rohit B; Kitchens, Kelly M; Swaan, Peter W et al. (2007) Surface acetylation of polyamidoamine (PAMAM) dendrimers decreases cytotoxicity while maintaining membrane permeability. Bioconjug Chem 18:2054-60 |
| Kitchens, Kelly M; Foraker, Amy B; Kolhatkar, Rohit B et al. (2007) Endocytosis and interaction of poly (amidoamine) dendrimers with Caco-2 cells. Pharm Res 24:2138-45 |
| Kitchens, Kelly M; Kolhatkar, Rohit B; Swaan, Peter W et al. (2006) Transport of poly(amidoamine) dendrimers across Caco-2 cell monolayers: Influence of size, charge and fluorescent labeling. Pharm Res 23:2818-26 |
| Kitchens, Kelly M; El-Sayed, Mohamed E H; Ghandehari, Hamidreza (2005) Transepithelial and endothelial transport of poly (amidoamine) dendrimers. Adv Drug Deliv Rev 57:2163-76 |
