POLY (AMIDO AMINE) DENDRIMERS: TRANSEPITHELIAL TRANSPORT MECHANISMS AND APPLICATIONS IN ORAL DRUG DELIVERY
Goldberg, Deborah Sweet
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Small molecule chemotherapy drugs used in clinical practice are plagued by dose-limiting side effects due to off-target toxicities. In addition, because of their low water solubility and poor bioavailability, they must be administered intravenously, leading to high treatment costs and recurring hospital visits. There is a significant need for therapies that improve the bioavailability of chemotherapy agents and enhance specific drug release in the tumor environment. Dendrimers, a class of highly-branched, nanoscale polymers, share many characteristics with traditional polymeric carriers, including water solubility, high capacity of drug loading and improved biodistribution. Poly (amido amine) (PAMAM) dendrimers have shown promise as oral drug carriers due to their compact size, high surface charge density and permeation across the intestinal epithelial barrier. Attachment of chemotherapy drugs to PAMAM dendrimers has the potential to make them orally administrable and reduce off-target toxicities. In this dissertation we investigate the transport mechanisms of PAMAM dendrimers and their potential in oral drug delivery. We demonstrate that anionic G3.5 dendrimers are endocytosed by dynamin-dependent mechanisms and their transport is governed by clathrin-mediated pathways. We show that dendrimer cellular internalization may be a requisite step for tight junction opening. We also demonstrate that conjugation of small poly (ethylene glycol) chains to anionic dendrimers decreases their transport and tight junction opening due to reduction in surface charge, illustrating that small changes in surface chemistry can significantly impact transepithelial transport. Knowledge of transport mechanisms and the impact of surface chemistry will aid in rational design of dendrimer oral drug delivery systems. The potential of dendrimers as oral drug delivery carriers is demonstrated by the evaluation of G3.5 PAMAM dendrimer-SN38 conjugates for oral therapy of hepatic colorectal cancer metastases, a pathology present in over 50% of colorectal cancer cases that is responsible for two-thirds of deaths. Conjugation of SN38, a potent chemotherapy drug with poor solubility and low bioavailability, to PAMAM dendrimers via a glycine linker increased intestinal permeability, decreased intestinal toxicity and showed selective release in the presence of liver carboxylesterase, illustrating that PAMAM dendrimers have the potential to improve the oral bioavailability of potent anti-cancer therapeutics.