Structure-Activity Relationship in Cationic Lipid Mediated Gene Transfection

Abstract

Non-viral synthetic vectors for gene delivery represent a safer alternative to viral vectors. Their main drawback is the low transfection efficiency, especially in vivo. Among the non-viral vectors currently in use, the cationic liposomes composed of cationic lipids are the most common. This review discusses the physicochemical properties of cationic lipids, the formation, macrostructure and specific parameters of the corresponding formulated liposomes, and the effect of all these parameters on transfection efficiency. The optimisation of liposomal vectors requires both the understanding of the biological variables involved in the transfection process, and the effect of the structural elements of the cationic lipids on these biological variables. The biological barriers relevant for in vitro and in vivo transfection are identified, and solutions to overcome them based on rational design of the cationic lipids are discussed. The review focuses on the relationship between the structure of the cationic lipid and the transfection activity. The structure is analysed in a modular manner. The hydrophobic domain, the cationic head group, the backbone that acts as a scaffold for the other domains, the linkers between backbone, hydrophobic domain and cationic head group, the polyethyleneglycol chains and the targeting moiety are identified as distinct elements of the cationic lipids used in gene therapy. The main chemical functionalities used to built these domains, as well as overall molecular features such as architecture and geometry, are presented. Studies of structure-activity relationships of each cationic lipid domain, including the authors', and the trends identified by these studies, help furthering the understanding of the mechanism governing the formation and behaviour of cationic liposomes in gene delivery, and therefore the rational design of new improved cationic lipids vectors capable of achieving clinical significance.

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

“…[25][26][27][28][29] Cationic lipids generally consist of polar head group and hydrophobic tails connected through the backbone (Fig. 1), while most of the backbone in earlier cationic lipids was classified into glycerol-type just as N- [2-[(1,5,10,14-tetraazatetradecane-1-yl) carbonylamino] ethyl]-N,Ndimethyl-2,3-bis(oleoyloxy)-1-propanaminium (DOSPA) and N- [2,3-dioleoyloxypropyl]-N,N,N-trimethylammonium chloride (DOTAP) 30,31) and cholesterol-type, such as 3β-[N-(N′,N′-dimethylaminoethyl) carbamoyl] cholesterol (DC-Chol). 32) Recently, phosphonate, 33) bile acid, 34) amino acids, 35,36) peptides, 37) pentaerythritol 38) and carbohydrate 39) were also successfully used as backbones in the design of cationic lipids, which can give a favorable gene delivery efficiency and low cytotoxicity.…”

Reconstituted influenza virus envelopes as an efficient carrier system for cellular delivery of small-interfering RNAs

“…In contrast, the escape of free or liposome-encapsulated siRNA from the endosome is generally inefficient and so far poorly understood. 54 Influenza virosomes for siRNA delivery J de Jonge et al…”

Influence of charge ratio of liposome/DNA complexes on their size after extrusion and transfection efficiency

“…21,22 Also, various studies have been conducted with the aim of synthesizing new cationic lipids with improved properties and studying structure-activity relationships. 23,24 However, since various factors influence the transfection efficiency, it is difficult to draw a definite conclusion about the influence of structural characteristics of lipids and physicochemical properties of liposome/DNA complexes on transfection efficiency. Finding an effective formulation thus remains mostly a process of trial and error.…”