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Abstract

In this thesis, we developed three polymer-based drug delivery platforms to address three health problems: oral immunotherapy for food allergy, tolerance against protein-based therapeutics, and tumor target therapy. As a major commensal bacterial metabolite, butyrate showed protective effect to the gut immunity and suppressed the activation of antigen presenting cells. However, there is an unmet need of developing an efficient formulation to deliver butyrate to either gastrointestinal (GI) tract or draining lymph nodes. In order to delivery butyrate to the GI tract, we developed two polymeric micelle platforms with butyrate ester in the core, and either neutral or negatively charged shell. We characterized the size and structure of the micelles. We validated both micelles released butyrate in the GI tract. Importantly, our formulations showed enhanced performance in the treatment of peanut allergy when combined with oral immunotherapy. Furthermore, we demonstrated the butyrate formulation up-regulated the expression of anti-microbial peptides and induced GATA3+ and RORγt+ regulatory T cells. To investigate the butyrate effect on inducing tolerogenic dendritic cells in the lymph node, we developed a statistical copolymer containing butyrate ester and mannose that targeted dendritic cells. We validated the release profile and the biodistribution of the polymer. The copolymer suppressed the activation of bone marrow-derived dendritic cells in vitro and induced tolerogenic dendritic cells in vivo. In a third project, we investigated tumor target delivery of paclitaxel, a famous chemotherapeutic drug, to address its problems in low solubility and adverse events. Collagen binding peptide has shown capability of targeting tumor environment. To explore extracellular matrix affinity-based cancer target therapy, we developed a water-soluble conjugate between collagen binding peptide and paclitaxel. We characterized the protein-drug conjugate and demonstrated the efficacy of the conjugate on cancer cells in vitro. Furthermore, we studied the protein-paclitaxel conjugate on mouse tumor model.

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