Cation Substitution in Cationic Phosphonolipids:  A New Concept To Improve Transfection Activity and Decrease Cellular Toxicity

Abstract

Cationic lipids have been shown to be an interesting alternative to viral vector-mediated gene delivery into in vitro and in vivo model applications. Prior studies have demonstrated that even minor structural modifications of the lipid hydrophobic domain or of the lipid polar domain result in significant changes in gene delivery efficiency. Previously, we developed a novel class of cationic lipids called cationic phosphonolipids and described the ability of these vectors to transfer DNA into different cell lines and in vivo. Up until now, in all new cationic lipids, nitrogen atoms have always carried the cationic or polycationic charge. Recently we have developed a new series of cationic phosphonolipids characterized by a cationic charge carried by a phosphorus or arsenic atom. In a second step, we have also examined the effects of the linker length between the cation and the hydrophobic domain as regards transfection activity. Transfection activities of this library of new cationic phosphonolipids were studied in vitro in different cell lines (HeLa, CFT1, K562) and in vivo using a luciferase reporter gene. A luminescent assay was carried out to assess luciferase expression. We demonstrated that cation substitution on the polar domain of cationic phosphonolipids (N --> P or As) results in significant increase in transfection activity for both in vitro and in vivo assays and decrease of cellular toxicity.

Preparation, Physicochemical Properties, and Transfection Activities of Tartaric Acid-Based Cationic Lipids as Effective Nonviral Gene Delivery Vectors

“…Preparation and Characterization of Cationic Liposomes Cationic lipids were often mixed with a neutral colipid dioleoylphosphatidylethanolamine (DOPE) to formulate into cationic liposomes. [42][43][44][45][46][47] The results of the particle size, size distribution and zeta potential of the cationic liposomes were shown in Table 1. The cationic formulation of two cationic lipids at lipid/DOPE ratio of 1 : 1 exhibited rather small hydrodynamic diameters 78.2 nm for T-C12-AH and 83.7 nm for T-C16-AH.…”

Preclinical Evidence that Use of TRAIL in Ewing's Sarcoma and Osteosarcoma Therapy Inhibits Tumor Growth, Prevents Osteolysis, and Increases Animal Survival

“…Experiments were done with the third-generation phosphonolipid transfection reagent KLN143, containing an ammonium polar head. It was used and formulated as previously described for the second generation of cationic phosphonolipids (29,30). Briefly, cationic lipids were dissolved in chloroform in a glass vial.…”

Single histidine residue in head-group region is sufficient to impart remarkable gene transfection properties to cationic lipids: evidence for histidine-mediated membrane fusion at acidic pH

“…Ever since Felgner et al 3 reported their pioneering development of cationic lipid-mediated gene delivery protocol in 1987, many reports aimed at developing more efficient cationic transfection lipids have appeared in the literature. [4][5][6][7][8][9][10] Recently, we have also developed efficient nonglycerol-based cationic transfection lipids. [11][12][13][14][15] In sharp contrast, details of cationic lipid-mediated transfection pathways still remain elusive.…”