Novel Cationic Lipids with Enhanced Gene Delivery and Antimicrobial Activity

Abstract

Cationic lipids facilitate plasmid delivery, and some cationic sterol-based compounds have antimicrobial activity because of their amphiphilic character. These dual functions are relevant in the context of local ongoing infection during intrapulmonary gene transfer for cystic fibrosis. The transfection activities of two cationic lipids, dexamethasone spermine (DS) and disubstituted spermine (D 2 S), were tested as individual components and mixtures in bovine aortic endothelial cells and A549 cells. The results showed a 3-to 7-fold improvement in transgene expression for mixtures of DS with 20 to 40 mol% D 2 S. D 2 S and coformulations with DS, dioleoyl phosphatidylethanolamine, and DNA exhibited potent bactericidal activity against Escherichia coli MG1655, Bacillus subtilis, and Pseudomonas aeruginosa PAO1, which was maintained in bronchoalveolar lavage fluid. Complete bacterial killing was demonstrated at ϳ5 M, including gene delivery formulations, with 2 orders of magnitude higher tolerance before eukaryotic membrane disruption (erythrocyte hemolysis). D 2 S also exhibited lipopolysaccharide (LPS) scavenging activity resulting in significant inhibition of LPS-mediated activation of human neutrophils with 85 and 65% lower interleukin-8 released at 12 and 24 h, respectively. Mixtures of DS and D 2 S can improve transfection activity over common lipofection reagents, and D 2 S has strong antimicrobial action suited for the suppression of bacterial-mediated inflammation.

Polyelectrolyte properties of filamentous biopolymers and their consequences in biological fluids

“…The opposite approach, to add multivalent counterions such as polycationic amphiphiles with strong negative curvature preference can also displace trapped cationic antibiotics 103 . Finally, efforts to reduce the positive charge of antimicrobial agents or to distribute it over larger surface have also shown potential to retain antibacterial activity in fluids with high concentrations of F-actin and DNA 67, 107–110 .…”

Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2+ Breast Cancer

“…Unfortunately, they did not show objective efficacy when used to treat tumors at other anatomic sites. [10] In addition, they elicited hematological toxicity in some cases [11] and some have been difficult to manufacture reproducibly at large scale. A cyclodextrin-based nanoparticle targeted to the human transferrin protein (hTf) was the first targeted siRNA delivery system to demonstrate anti-cancer efficacy at sites other than the liver (i.e., melanoma).…”

Structure–Function Relationships of New Lipids Designed for DNA Transfection

“…Concerning cationic lipofection, innumerable lipid structures already exist, novel structures are constantly being synthesized, and new formulations are persistently tested. [10][11][12][13][14][15] If a new lipid with promising transfection activity and low toxicity is identified, the next step is to elucidate its structurefunction relationship. [16,17] Investigation of the physicochemical properties turned out to be a domain that can correlate structural characteristics with transfection results.…”