Synthesis of Novel Acid-Sensitive Lipids and Their Application in Drug and Gene Delivery
Abstract
The synthesis and drug and gene delivery applications of four acid-labile, vinyl ether containing lipids is described. Under low pH conditions, enhanced contents release was observed from dioleoylphosphatidyl ethanolamine (DOPE) liposomes stabilized with doping quantities of two novel acid-labile poly(ethylene glycol)-lipid conjugates, relative to a non-labile analog and release at neutral pH. Cleavage of the vinyl ether linkage removes the poly(ethylene glycol) corona from the surface, thereby destabilizing the liposomes, inducing contents release and membrane-membrane fusion. Contents release was examined in vitro using a fluorescence dequenching assay and enhanced cytoplasmic delivery was observed via fluorescence microscopy. An acid-labile cationic DNA binding lipid exhibited enhanced transgene expression relative to a non-hydrolysable analog. These results showed that acid-triggered vinyl ether cleavage is a viable strategy for enhancing liposomal contents release, cytoplasmic delivery, and transgene expression.
Degree
Ph.D.
Advisors
Thompson, Purdue University.
Subject Area
Organic chemistry|Biochemistry
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