RESULTS:
1 - 5 of 5 for ""cationic lipid""
Structure-Activity Relationship in Cationic Lipid Mediated Gene Transfection
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.
Cationic Lipid Vectors for Plasmid DNA Delivery
Successful gene therapy depends on efficient gene transfer vectors. Viral vectors and non-viral vectors have been investigated extensively. Cationic lipids are non-viral vectors which resemble traditional pharmaceuticals display little immunogenicity and have no potential for viral infection. However toxicity and low transfection efficiency are two barriers limiting the clinical applications of cationic lipids. Over the last decade hundreds of cationic lipids have been synthesized to address these problems. In this brief review we summarized recent research results concerning the structures of DNA / liposomes complexes some important strategies used to design different classes of cationic lipids and use of disulfide cationic lipids in plasmid DNA delivery.
The Design of Cationic Lipids for Gene Delivery
Synthetic gene delivery vectors are gaining increasing importance in gene therapy as an alternative to recombinant viruses. Among the various types of non-viral vectors cationic lipids are especially attractive as they can be prepared with relative ease and extensively characterised. Further each of their constituent parts can be modified thereby facilitating the elucidation of structure-activity relationships. In this forward-looking review cationic lipid-mediated gene delivery will mainly be discussed in terms of the structure of the three basic constituent parts of any cationic lipid: the polar headgroup hydrophobic moiety and linker. Particular emphasis will be placed on recent advances in the field as well as on our own original contributions. In addition to reviewing critical physicochemical features (such as headgroup hydration) of monovalent lipids the use of headgroups with known nucleic-acid binding modes such as linear and branched polyamines aminoglycosides and guanidinium functions will be comprehensively assessed. A particularly exciting innovation in linker design is the incorporation of environment-sensitive groups the intracellular hydrolysis of which may lead to more controlled DNA delivery. Examples of pH- redox- and enzyme-sensitive functional groups integrated into the linker are highlighted and the benefits of such degradable vectors can be evaluated in terms of transfection efficiency and cationic lipid-associated cytotoxicity. Finally possible correlations between the length and type of hydrophobic moiety and transfection efficiency will be discussed. In conclusion it may be foreseen that in order to be successful the future of cationic lipid-based gene delivery will probably require the development of sophisticated virus-like systems which can be viewed as “programmed supramolecular systems” incorporating the various functions required to perform in a chronological order the different steps involved in gene transfection.
New Chemoenzymatic Synthesis of (±)-N-(2-hydroxyethyl)-N,N-dime thyl- 2,3-bis(tetradecyloxy)-1-propanammonium Bromide (DMRIE)
Background: Cytofectins are a class of positively charged lipid molecules that can facilitate the functional entry of polynucleotides macromolecules and small molecules into living cells escaping lysosomal degradation. One of the most potent cytofectins dimyristoyl Rosenthal inhibitor ether (DMRIE) is presently being used to deliver differents active molecules into animal and human diseased tissues. To our knowledge two synthetic routes for the preparation of DMRIE have so far been reported. One of them is based on the reaction of epichlorhydrin with either dimethylamine chloride or dimethylamine using an alkaline solution as solvent. The main disadvantage of these routes is the formation of 3-(NN-diamino)-12-propanediol. In summary the synthetic routes mentioned use epichlorohydrin or glycidol as starting materials both of which have been described as carcinogenic agents. Additionally sometimes the reaction conditions are drastic. An alternative route for the preparation of other cytofectins is the use of glycerol as the starting material. Glycerol is a non-carcinogenic compound but its use as starting material results in an increased number of steps of this reaction generating an increase in the total time of synthesis and the formation of a greater amount of waste and scrap. Based on the above here we propose a new chemoenzymatic synthetic strategy using glycerol as a starting material. Methods: Initially glycerol and vinyl benzoate were mixed in presence of Mucor miehei lipase (Lipozyme) it is converted into corresponding mono-benzoate (±)-1. Finally DMRIE was obtained by the reaction of bromide (±)-3 with 2- dimethylaminoethanol (DMAE). Results: We studied the stability of compound (±)-1 under the working conditions applied in the preparation of intermediate alcohol (±)-2. Additionally we study different experimental parameters. Conclusion: In summary a new chemoenzymatic synthetic route was developed for the DMRIE using glycerol as the starting material. We studied and optimized various experimental parameters of the various synthetic steps and reached to develop the methodology to multigram scale which compared to processes reported so far has the advantages of fewer synthetic steps the use of less aggressive reagents environment and generating fewer waste allowed to obtain the desired product; which results in a viable method for synthesizing analogs to DMRIE.
Application of DODMA and Derivatives in Cationic Nanocarriers for Gene Delivery
With the development of nanotechnology nano-biomaterials have shown good development prospects in gene therapy. Cationic lipids include a group of amphiphiles that exhibit positive charge which interacts with negatively charged DNA/RNA leading to the formation of complexes containing condensed gene materials. Cationic liposomes complexed with gene materials are promising non-viral carriers for gene therapy. As an environmentally ionized cationic lipid N-[1-(23-dioleyloxy)propyl]-NNN-trimethylammonium chloride (DOTMA) shows positive charge at low pH with moderate pKa value due to the headgroup of tertiary amine. It makes 12-dioleyloxy-NN-dimethyl-3- aminopropane (DODMA) very effective in encapsulating nucleic acids during synthesis by temporarily reducing pH. Thus lipid nanoparticles with DODMA can have neutral or low zeta potential at physiological pH. These remarkable structure-dependent properties have far reaching application potential in gene therapy. This review summarizes the synthesis methods and structure characteristics of DODMA and derivatives and illustrates their applications in gene delivery.