Access Type

Open Access Embargo

Date of Award

January 2019

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemical Engineering and Materials Science

First Advisor

Haipeng . Liu

Abstract

Eliminating the need for external delivery systems, self-delivery drug amphiphiles represent a simple yet effective approach designed to overcome the various biological barriers for drug delivery. The ability to program the molecular structures and the physicochemical properties, which control the interactions between the drug amphiphiles and their biological surroundings has attracted significant research interests. In this work, we constructed several amphiphilic drugs including chemotherapeutic and immunotherapeutic agents. These amphiphiles exhibited interesting interactions with their biological surroundings. Amphiphiles self-assemble into spherical micelle structures in aqueous solution. However, in the presence of complexed biological fluids, they also possess a strong affinity toward albumin protein and plasma membrane. By controlling the molecular structures which govern the three-way equilibrium, self-delivery drugs/vaccines overcoming multiple biological barriers were designed and tested in vitro and in vivo. Employed endogenous albumin protein as a drug carrier, self-delivery chemotherapeutic drug amphiphiles (e.g. amphiphilic doxorubicin) were firstly investigated. High levels of tumor-specific and extended circulating half-life facilitated doxorubicin-induced cytotoxicity and anti-cancer efficacy. Importantly, it was the first report on lipid-based targeting subcellular mitochondria which filled the gap of intracellular tracking using lipoplex approaches. Translating from albumin-based self-delivery strategy, amphiphilic lipid-based immunosuppressive drugs and peptides were studies on several immune disease models. Amphiphilic peptides were observed to accumulate in the antigen presenting cells (APCs) in the lymph nodes (LNs), enhance the potency and duration of peptide antigen presentation by APCs, and induce antigen-specific immune tolerance that controlled both T-cell- and B-cell-mediated immunity. Moreover, immunization with an amphiphilic insulin B chain 9-23 peptide, an immunodominant CD4+ T cell epitope in non­obese diabetic (NOD) mice successfully restored antigen-specific immune tolerance delaying the onset of Type 1 Diabetes (T1Ds). Overall, those self-delivery amphiphilic drugs provided a simple approach to improve the bioavailability, bioaccessibility, and biocompatibility of the pharmaceutical payloads, which will be emerged as a novel design principle for drug delivery in the future.

Available for download on Wednesday, January 12, 2022

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