A series of cationic sterol lipids with gene transfer, bactericidal and anti-endotoxin activity.

Format:

Book

Thesis/Dissertation

Author/Creator:

Randazzo, Renee.

Contributor:

Diamond, Scott L., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Chemical engineering.

0542.

Penn dissertations--Chemical and biomolecular engineering.

Chemical and biomolecular engineering--Penn dissertations.

Local Subjects:

Penn dissertations--Chemical and biomolecular engineering.

Chemical and biomolecular engineering--Penn dissertations.

0542.

Physical Description:

104 pages

Contained In:

Dissertation Abstracts International 70-06B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

The amphiphilic nature of cationic lipids promotes their utility in a variety of biological applications. In this work, we examine three of these applications with the use of a family of cholic acid and spermine derived cationic sterol lipids. Based on literature precedence for the use of cationic lipids and overlap in the basic design requirements for each area, we chose to study gene delivery, antibacterial properties, and endotoxin antagonism. We designed, synthesized, and characterized the cationic sterol lipids to allow for the study of varying structural features in each application. Of the five compounds that were synthesized, four contained structural features focused on varying hydrophobicity and incorporation of a degree of unsaturation on the sterol ring. The fifth compound was a bis-substituted analogue of the most hydrophilic in the family. When formulated as gene delivery vectors, the inclusion of the double bond significantly promoted transfection efficiency. Co-formulation of the bis-substituted compound with its mono-substituted analogue also produced a significant enhancement in activity over the use of either compound independently. When introduced to both gram-positive and gram-negative bacteria, the compound family possessed significant bacteriostatic and bactericidal properties. While the bactericidal potential of the compounds did appear to increase with increasing hydrophobicity, in the presence of serum or in sputum isolates from the lungs of cystic fibrosis patients the compounds that included a degree of unsaturation were able to better retain their activity. In the context of endotoxin antagonism, the entire compound family was able to achieve significant suppression of lipopolysaccharide-induced immune response. The most active inhibitor was the bis-substituted compound. Among the mono-substituted lipids, those including the degree of unsaturation were the most active suppressors of the immune response. This work represents some significant findings relevant to the design of cationic sterol lipids for gene delivery, as antibacterials, and as endotoxin antagonists.

Notes:

Thesis (Ph.D. in Chemical and Biomolecular Engineering) -- University of Pennsylvania, 2009.

Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3661.

Adviser: Scott L. Diamond.

Local Notes:

School code: 0175.

ISBN:

9781109236217

Access Restriction:

Restricted for use by site license.