Lipid Carriers for Gene Therapy

Abstract

A wide variety of lipid molecules used as gene carriers has been reported and compared over the last twenty years. This review highlights a few examples of mechanistic analysis applied to the study of lipid carriers. The modular nature of the lipid structure offers itself up to a controlled, systematic analysis. Key to exploring structural variants is the understanding of the role each component and module plays in the formation of the lipoplex structure itself and their roles in the transfection pathway. Firstly, the lipid carrier must be able to package, and release into the cell its nucleic acid cargo. Uptake of lipoplexes into cells involves endocytic processes that lead inevitably to endosomal/liposomal degradation of the nucleic acid contents, unless lipid structures and designs are optimised to facilitate their release into the cytoplasm. Testing of possible endosomal escape mechanisms has led to improved lipid designs. For example, it was predicted that mixing of cationic lipids with shorter alkyl tails (<C18) from liposomes with the endosomal bilayer during the transfection process within the endosome should promote membrane fluidity, enhancing plasmid release and transfection efficiency. This hypothesis has been borne out numerous times. "Smart" molecules that respond to cellular cues such as endosomal pH have now been developed that appear to offer exciting opportunities for the future role of lipoplexes in clinical applications of gene therapy. The variability of cultured cell and model biological systems remains a challenge in designing improved lipids of general utility.

Uptake and intracellular release kinetics of liposome formulations in glioma cells

“…It is well acknowledged that liposome stability and retention capacity are inversely related to bilayer membrane fluidity (Drummond et al, 1999;Lian and Ho, 2001;Waterhouse et al, 2005;Hart, 2005;Kobayashi et al, 2007). Therefore, the greater membrane stability of DSPC containing liposomes (formulation B) may have impaired the intracellular destabilization of vesicles, and thus, the capacity of the liposomal carriers to release their content.…”

Sclareol induces apoptosis in human HCT116 colon cancer cells in vitro and suppression of HCT116 tumor growth in immunodeficient mice

“…Our choice of liposomes as lipid-based drug carriers to deliver sclareol was motivated by their well documented ability to deliver bioactive compounds in a targeted manner, and their favourable physicochemical properties that typically result in improvement of the pharmacokinetic properties and pharmacological response of the encapsulated drugs, while reducing drug-associated side effects (for recent reviews, see refs. [20][21][22][23][24]). …”

DOTAP/DOPE and DC-Chol/DOPE lipoplexes for gene delivery studied by circular dichroism and other biophysical techniques

“…Cationic lipids and cationic polymers have been extensively studied for gene transfer experiments, during the last two decades [4][5][6][7][8][9] . In spite of a few limitations, such as a relatively low transfection rate and some intrinsic cell toxicity, these cationic agents are considered as a valid alternative to viral vectors [10][11][12].…”