Novel pH-sensitive cationic lipids with linear ortho ester linkers for gene delivery

Abstract

In an effort to develop pH-sensitive lipoplexes for efficient gene delivery, we report three novel cationic lipids containing a linear ortho ester linker that conjugates either the headgroup (Type I) or one hydrocarbon chain (Type II) with the rest of the lipid molecule. The cationic lipids carry either an iodide or a chloride counterion. Compared to our previously reported cyclic ortho ester linker, the linear ortho ester linker facilitated the construction of cationic liposomes and lipoplexes with different helper lipids. The chloride counterion not only facilitated the hydration of the lipid films during liposome construction, but also enhanced the hydrolysis of the ortho ester linker in the lipoplexes. After incubation at endosomal pH 5.5, the Type I lipoplexes aggregated and destabilized the endosome-mimicking model liposomes, but not the Type II lipoplexes. The helper lipids (DOPE or cholesterol) of the lipoplexes enhanced the pH-sensitivity of the Type I lipoplexes. In CV-1 cells (monkey kidney fibroblast), the Type I ortho ester-based lipoplexes, especially those with the chloride counterion, significantly improved the gene transfection efficiency, in some cases by more than 100 fold, compared to their pH-insensitive counterparts consisting of DOTAP. The gene transfection efficiency of the ortho ester-based lipoplexes was well correlated with their rate of aggregation and membrane destabilization in response to the endosomal pH 5.5.

trans-2-Aminocyclohexanol-based amphiphiles as highly efficient helper lipids for gene delivery by lipoplexes

“…In comparison, the reported lipoplexes DOTAP/DOPE/DNA and DOTAP/cholesterol/DNA (N/ P = 5/1) were administered as pH-insensitive controls [33,54]. Furthermore, lipoplexes DOTAP/9/DNA and DOTAP/10/DNA (N/P = 5/1), which contained TACH analogs (9) [21,22] or (10) that do not switch conformation were also characterized in an effort to decipher the contribution of conformation switch to the gene transfection by TACH lipids.…”

Physicochemical and biological characterization of 1,2-dialkoylamidopropane-based lipoplexes for gene delivery

“…To overcome these limitations, different structures of cationic lipids were synthesized and evaluated for lipofection effectiveness in the past two decades [6,7,18,20,23,42,43]. Moreover, the physicochemical properties of these lipids and their complexes with nucleic acids (DNA, oligonucleotides, and siRNA) were investigated in an attempt to derive a structure activity relationship [4,27,38].…”

A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery

“…The Type I lipoplexes aggregated and destabilized at the endosomal pH (pH 5.5), but the Type II lipoplexes were not. The Type I ortho ester-based lipoplexes containing helper lipids, DOPE or cholesterol and with the chloride counter ion, significantly improved the gene transfection efficiency, more than 100 fold in CV-1 cells (monkey kidney fibroblast) (Chen et al, 2012).…”

“…Similar other reports also describe importance of pH sensitivity within liposomal membrane for intracellular gene transfection (Sakaguchi et al, 2008a,b,c). Chen et al (2012) developed pH-sensitive lipoplexes for efficient gene delivery with the three novel cationic lipids containing a linear ortho ester linker that conjugates either the head group (Type I) or one hydrocarbon chain (Type II) with the rest of the lipid molecule. The cationic lipids bear counter ion either an iodide or a chloride.…”