Targeted delivery of oligodeoxynucleotides to mouse lung endothelial cells in vitro and in vivo.
Pulmonary endothelium plays an important role in the maintenance of normal pulmonary physiology and its dysfunction is involved in a number of pulmonary diseases. Correction of endothelial dysfunction via antisense oligodeoxynucleotides (ODN) is dependent on the development of a delivery vehicle that can efficiently deliver the ODN to pulmonary endothelium with minimal toxicity. To this end, we have developed a novel lipidic vector that is highly efficient in targeted delivery of ODN to pulmonary endothelium. This is based on a method that utilizes an ionizable aminolipid (1,2-dioleoyl-3-dimethylammonium propane) and an ethanol-containing buffer system for encapsulating large quantities of polyanionic ODN in lipid vesicles. An endothelium-specific antibody (273-34A) is incorporated into the lipid vesicles via a distearoylphosphatidylethanolamine-poly(ethylene glycol) spacer. The 273-34A antibody efficiently mediated delivery of ODN to mouse lung endothelial cells in vitro and in vivo. Furthermore, systemic administration of this formulation is associated with minimal hematological toxicities and induces little acute change in systemic and pulmonary hemodynamics. These results provide a basis for lipid-mediated delivery of ODN for the treatment of pulmonary diseases. They also suggest the utility of this approach as a research tool to characterize the function of genes in the pulmonary endothelium.
Wilson
Annette
A
Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Zhou
Wen
W
Champion
Hunter C
HC
Alber
Sean
S
Tang
Zhi-Lue
ZL
Kennel
Steven
S
Watkins
Simon
S
Huang
Leaf
L
Pitt
Bruce
B
Li
Song
S
D000818:Animals; D015536:Down-Regulation; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000737:chemistry; D008081:Liposomes / Q000378:metabolism; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics*; D013997:Time Factors
D008070:Lipopolysaccharides; D008081:Liposomes; D009841:Oligonucleotides; D018799:Intercellular Adhesion Molecule-1