title: Tuning the self-assembling of pyridinium cationic lipids for efficient gene delivery into neuronal cells.
abstract: We are reporting a new set of biocompatible, low-toxicity pyridinium cationic lipids based on a dopamine backbone on which hydrophobic alkyl tails are attached via an ether linkage. Due to their optimized hydrophilic/hydrophobic interface and packing parameter, the new lipids are able to strongly self-assemble either alone or when coformulated with colipids DOPE or cholesterol. The supra-molecular assemblies generated with the novel pyridinium amphiphiles were characterized in bulk and in solution via a combination of techniques including DSC, nanoDSC, SAXS, TOPM, TEM, DLS, zeta potential, and electrophoretic mobility measurements. These cationic bilayers can efficiently condense and deliver DNA to a large variety of cell lines, as proven by our self-assembling/physicochemical/biological correlation study. Using the luciferase reporter gene plasmid, we have also conducted a comprehensive structure-activity relationship study, which identified the best structural parameters and formulations for efficient and nontoxic gene delivery. Several formulations greatly surpassed established transfection systems with proved in vitro and in vivo efficiency, being able to transfect a large variety of malignant cells even in the presence of elevated levels of serum. The most efficient formulation was able to transfect selectively primary rat dopaminergic neurons harvested from nucleus accumbens, and neurons from the frontal cortex, a premise that recommends these synthetic vectors for future in vivo delivery studies for neuronal reprogramming.
authors.affiliation: Department of Chemistry, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
authors.forename: Sushma
authors.initials: S
authors.lastname: Savarala
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Wunder
authors.forename: Marc A
authors.initials: MA
authors.lastname: Ilies
mesh_terms: D000818:Animals; D002412:Cations / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D049409:Luciferases, Firefly / Q000096:biosynthesis / Q000235:genetics; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D009215:Myometrium / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology; D010316:Particle Size; D061251:Primary Cell Culture; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013501:Surface-Active Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D014162:Transfection / Q000379:methods*
chemical_list: D002412:Cations; D005227:Fatty Acids; D008081:Liposomes; D011726:Pyridinium Compounds; D013501:Surface-Active Agents; D049409:Luciferases, Firefly