fulltext.study @t Gmail

The influence of the structural orientation of amide linkers on the serum compatibility and lung transfection properties of cationic amphiphiles

Paper ID Volume ID Publish Year Pages File Format Full-Text
7360 550 2011 10 PDF Available
Title
The influence of the structural orientation of amide linkers on the serum compatibility and lung transfection properties of cationic amphiphiles
Abstract

Understanding the structural parameters of cationic amphiphiles which can influence gene transfer efficiencies of cationic amphiphiles continues to remain important for designing efficient liposomal gene delivery reagents. Previously we demonstrated the influence of structural orientation of the ester linker (widely used in covalently tethering the polar head and the non-polar tails) in modulating in vitro gene transfer efficiencies of cationic amphiphiles. However, our previously described cationic amphiphiles with ester linkers failed to deliver genes under in vivo conditions. Herein we report on the development of a highly serum compatible cationic amphiphile with circulation stable amide linker which shows remarkable selectivity in transfecting mouse lung. We also demonstrate that reversing structural orientation of the amide linker adversely affects both serum compatibility and the lung selective gene transfer property. Dynamic laser light scattering and atomic force microscopic studies revealed smaller average hydrodynamic sizes of the liposomes of transfection efficient lipid than those for the liposomes of transfection incompetent analog (148 ± 1 nm vs 214 ± 4 nm). Average surface potential of the liposomes of transfection competent amphiphiles were found to be significantly higher than that for the liposomes of transfection incompetent analog (10.7 ± 5.4 mV vs 2.8 ± 1.3 mV, respectively). Findings in fluorescence resonance energy transfer and dye entrapment experiments support lower rigidity and higher biomembrane fusogenicity of the liposomes of the transfection efficient amphiphiles. Importantly, cationic lipoplexes of the novel amide-linker based amphiphile exhibited higher mouse lung selective gene transfer properties than DOTAP, one of the widely used commercially available liposomal lung transfection kits. In summary, the present findings demonstrate for the first time that amide linker structural orientation profoundly influences the serum compatibility and lung transfection efficiencies of cationic amphiphiles.

Keywords
Serum compatible lipofectins; Selective lung transfection; Linker orientation effect; Fluorescence resonance energy transfer; Biomembrane fusogenicityChol, cholesterol; DCM, dichloromethane; DMEM, Dulbecco’s modified Eagle’s medium; MEM, minimum essential
First Page Preview
The influence of the structural orientation of amide linkers on the serum compatibility and lung transfection properties of cationic amphiphiles
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 32, Issue 22, August 2011, Pages 5231–5240
Authors
, , , , , ,
Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering