ABSTRACT
Several new classes of pyridinium cationic lipids were synthesized and tested as gene delivery agents. They were obtained through a procedure that generates simultaneously the heterocyclic ring and the positively charged nitrogen atom, using lipophilic pyrylium salts as key intermediates that react with primary amines, yielding pyridinium salts. The choice of the appropriately substituted primary amine, diamine or polyamine, allows the design of the shape of the final lipids, gemini surfactants, or lipophilic polycations. We report also a comprehensive structure-activity relationship study that identified the most efficient structural variables at the levels of the hydrophobic anchor, linker, and counterion for these classes of pyridinium cationic lipids. This study was also aimed at finding the best liposomal formulation for the new transfection agents.
Subject(s)
Drug Carriers/chemical synthesis , Gene Transfer Techniques , Lipids/chemical synthesis , Onium Compounds/chemical synthesis , Polymers/chemical synthesis , Pyridines/chemical synthesis , Pyrones/chemical synthesis , Surface-Active Agents/chemical synthesis , Cations , Cell Line, Tumor , Drug Carriers/chemistry , Humans , Lipids/chemistry , Liposomes/chemistry , Onium Compounds/chemistry , Polymers/chemistry , Pyridines/chemistry , Pyrones/chemistry , Structure-Activity Relationship , Surface-Active Agents/chemistryABSTRACT
Three series of pyridinium cationic lipids useful as nonviral gene delivery agents were prepared by reaction of pyrylium salts with aminodiols, followed by acylation with fatty acyl chlorides. On the basis of this set of compounds, we undertook a comprehensive structure-activity relationship study at the level of the linker, hydrophobic anchor, and counterion in order to identify the structural elements that generate the highest transfection efficiency for this new type of cationic lipid. The results revealed that when formulated with cholesterol at a 1:1 molar ratio, the 1-(1,3-dimyristoyloxyprop-2-yl)-2,4,6-trimethylpyridinium, under the form of hexafluorophosphate (5AMyr) or chloride (5DMyr), was able to transfect NCI-H23 lung carcinoma with efficiencies surpassing classic DOTAP-based formulations and with lower cytotoxicity. Subsequent tests on other malignancies yielded similarly promising results.
Subject(s)
Diglycerides/chemical synthesis , Drug Carriers/chemical synthesis , Gene Transfer Techniques , Lipids/chemical synthesis , Pyridinium Compounds/chemical synthesis , Cations , Cell Line, Tumor , Cell Survival/drug effects , Cholesterol/chemistry , DNA/administration & dosage , DNA/chemistry , Diglycerides/chemistry , Diglycerides/toxicity , Drug Carriers/chemistry , Drug Carriers/toxicity , Humans , Lipids/chemistry , Liposomes , Molecular Structure , Pyridinium Compounds/chemistry , Pyridinium Compounds/toxicity , Structure-Activity Relationship , Transfection , UltrasonicsABSTRACT
Gene therapy will change medicine by treating the diseases at their core levels revolutionizing the way to deliver functional proteins. The development of this technology relies in designing optimal systems for DNA transfer and expression (transfection), cationic lipids being a promising alternative. Being safer than viral vectors, they also allow the delivery of larger plasmids and can be easily GMP-manufactured and stored. The main problem associated with the use of these vectors is their transfection efficiency, which is still inferior to viral methods. In this paper we present an overview of the correlations between the chemical structure and biological activity for the principal classes of cationic lipids. Key issues in the design of this class of transfection agents are presented, as well as the future trends.
