Browsing Theses and Dissertations School of Pharmacy by Title "Mechanisms of Dendrimer-Mediated Oral Drug Delivery"
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Mechanisms of Dendrimer-Mediated Oral Drug DeliveryOral administration of chemotherapeutics remains a challenge despite the benefits for both the patient and health care system. To overcome the poor solubility and low oral bioavailability of anti-cancer drugs, polymeric delivery systems have been investigated. Dendrimers, a class of highly branched polymers, have proven useful for drug delivery because of their compact, nanoscopic size. Specifically, poly(amidoamine) (PAMAM) dendrimers have been shown to permeate the intestinal epithelium indicating potential as oral drug delivery carriers. While studies in our laboratory have determined the effects of surface modification on dendrimer transport and uptake, a large gap in knowledge exists in the transport and cytotoxicity mechanisms of PAMAM dendrimers. Additionally, alternatives to PAMAM dendrimers such as biodegradable poly-L-lysine (PLL) dendrimers have yet to be investigated for use in oral delivery. In this work we report the mechanisms of tight junction modulation by PAMAM dendrimers. While anionic dendrimers modulated tight junction proteins, cationic dendrimers opened tight junctions through phospholipase C-mediated calcium signaling allowing for paracellular small molecule transport. In comparison, cationic PLL dendrimers also allowed for small molecule transport with similar decreases in transepithelial electrical resistance. Small generation PAMAM and PLL dendrimers (16 and 32 surface amines) activated Caspase-3 and -7 resulting in apoptosis. In contrast, PLL dendrimers showed less long term toxicity compared to PAMAM dendrimers illustrating the benefits of dendrimer biodegradability. We also investigated the mechanisms of PLL dendrimer internalization and subcellular trafficking and the impact conjugation had on these mechanisms. The pH and enzymes present vary within different intracellular vesicles. Knowledge of the environment a drug delivery system will encounter is crucial for proper drug release. While PLL dendrimers were internalized via cholesterol- and dynamin-mediated endocytosis and macropinocytosis, conjugation site impacted uptake and localization. By conjugating a model compound to either the dendrimer core or surface, the uptake and transport properties of the delivery system were modified. Core-conjugated dendrimers had higher uptake and localized to the lysosomes and nucleus while surface conjugation resulted in higher transport and less accumulation in lysosomes. This research provides important knowledge for designing an effective dendrimer-based oral drug delivery system.