Factors influencing the efficiency of cationic liposome-mediated intravenous gene delivery

Abstract

We have characterized the relationships between the design of cationic liposomes as a gene transfer vehicle, their resulting biodistribution and processing in animals, and the level and sites of gene expression they produce. By redesigning conventional cationic liposomes, incorporating cholesterol (chol) as the neutral lipid and preparing them as multilamellar vesicles (MLV), we increased the efficiency of cationic liposome:DNA complex (CLDC)-mediated gene delivery. Expression of the luciferase gene increased up to 1,740-fold and of the human granulocyte-colony stimulating factor (hG-CSF) gene up to 569-fold due to prolonged circulation time of injected CLDC, and increased uptake and retention in tissues. The level of gene expression per microgram of DNA taken up per tissue was 1,000-fold higher in lung than in liver, indicating that in addition to issues of delivery and retention of injected DNA, tissue-specific host factors also play a central role in determining the efficiency of expression. Vascular endothelial cells, monocytes, and macrophages are the cell types most commonly transfected by intravenous injection of CLDC.

The role of tissue macrophages in the induction of proinflammatory cytokine production following intravenous injection of lipoplexes

“…39 After intravenous administration of lipoplex, the lung shows the highest amount of gene expression among various organs and the lung endothelial cells are the main contributor to transgene expression. [1][2][3] We and others have confirmed that the gene expression level in the lung is 1000-10 000 times higher than that in the liver and spleen (data not shown). [1][2][3] Therefore, intravenous administration of lipoplex may be a promising gene delivery method to treat pulmonary diseases.…”

“…[1][2][3] Therefore, increasing attention has focused on the development of efficient in vivo gene delivery systems. However, intravenous administration of cationic lipid vectors containing plasmid DNA has been shown to initiate potent cytokine responses.…”

Comparison between intratracheal and intravenous administration of liposome–DNA complexes for cystic fibrosis lung gene therapy

“…Possible explanations that may account for the rapid decline in expression observed here and in other studies include: (1) loss of plasmid DNA and/or RNA from the transfected cells; (2) down-regulation of the CMV promoter; or (3) loss of transfected cells due to necrosis. Previous studies 21,22 reported that MLV will improve gene delivery over LUV using various cationic liposome formulations in vitro and in vivo. Our study also showed a better performance of MLV in vivo following i.v.…”

Co-polymer of histidine and lysine markedly enhances transfection efficiency of liposomes

“…The discovery of new lipids, 12 the substitution of the helper lipid, cholesterol, for DOPE, 13 and steric stabilization with polyethylene glycol 14 have enhanced in vivo transfection efficiency of liposomes. The addition of polyl-lysine or protamine to cationic liposome carriers has also markedly enhanced the transfection efficiency of liposomes.…”