Date on Master's Thesis/Doctoral Dissertation

5-2012

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Chemistry

Committee Chair

Nantz, Michael H.

Author's Keywords

Cationic aminooxy lipid; Click chemistry; Liposome; Gene transfection; Stabilization; Nano reactor

Subject

Lipids; Lipids--Synthesis; Liposomes

Abstract

This dissertation describes research focused on the synthesis, polymerization and applications of cationic aminooxy lipids. An efficient and convenient method was developed to stabilize liposomes using 'click chemistry'. The 'click stabilized liposomes' are fortified via covalent crosslinks generated between aldehyde and aminooxy functionalities in the lipid bilayers. Compared to untreated liposomes (i.e., no lipid-lipid bonding), the 'click' stabilized liposomes are considerably more stable against surfactant-mediated liposome disruption or serum-mediated liposome aggregation. Stabilized liposomes also can react with 'clickable' targeted ligands on the liposome surface for specific organ (e.g. breast cancer cells or liver) targeting. In this thesis, I have explored the feasibility of using the click stabilized liposomes in three different applications: i) colonic targeted delivery ii) gene vector iii) enzyme nanoreactor. This dissertation is divided into six chapters. Chapter 1 gives a review of liposomes and liposome stabilization. Chapter 2 describes the synthesis and characterization of cationic aminooxy compounds 2.1 and 2.2 as the headgroup domains of prototype lipids. Chapter 3 describes the synthesis, characterization and hydrolysis of cationic aminooxy enol ether lipids 3.1 and 3.2. The liposomes formulated from lipid 3.2 were stabilized using a pH-triggered lipid polymerization strategy. Chapter 4 describes the synthesis and characterization of a variety of aminooxy lipids and dextran polyaldehydes (DPAs). The liposomes formulated from lipids 4.1 were stabilized by simply mixing with DPAs. The resultant 'click' stabilized liposomes have potential applications such as drug carriers for colonic targeted delivery and as nano-reactors. Chapter 5 focuses on applying 'click' stabilized liposomes as gene carriers. The initial results of in vitro gene transfection revealed that the stabilized lipoplexes formulated from lipid 4.1 successfully transfected MFC-7 cells, but with lower transfection potency. A liver-targeted ligand 5.2 based on lactose was synthesized for future in vivo gene transfection applications. Chapter 6 details all experimental procedures and approaches used for compound characterizations.

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