Aliphatic ionenes as gene delivery agents: elucidation of structure-function relationship through modification of charge density and polymer length.
Polycation-based gene delivery agents are generally polydisperse populations whose properties are averaged among the different molecular weight species. Therefore, to understand the physicochemical properties of polycations and their relationships to cellular gene transfer, one needs to control the molecular weight of the polymer as well as its cationic charge density. To investigate the structure-function correlation of polycations with respect to the degree of polymerization (DP) and charge density, a series of model materials based on aliphatic ionenes was synthesized and fractionated into distinct molecular weight fractions with DP range from 14 to 32. The aliphatic ionene fractions and their polyelectrolyte complexes (PEC) with DNA were studied using physicochemical and biological methods. Ionene polymers were shown to possess low cytotoxicity (minimal viability of the P388D1 murine macrophage cells 80%). DP and charge density of the ionenes were shown to be the factors of effective control of PEC dissociation in water-salt solutions, with a diminished role of charge density upon lengthening the ionene chain. These polymer characteristics were also important for DNA-ionene PEC resistivity to DNase activity and the ability of ionenes to serve as gene delivery vectors in vitro and exhibited good correlation with the results of salt-induced dissociation of PEC. These data may be useful for developing correlations and mathematical models to predict synthetic gene delivery vector efficiency.
Zelikin
Alexander N
AN
M. V. Lomonosov Moscow State University, Chemistry Department, Vorob'evi Gori V-234, 119899, Russia.
Putnam
David
D
Shastri
Prasad
P
Langer
Robert
R
Izumrudov
Vladimir A
VA
D000818:Animals; D000838:Anions / Q000737:chemistry*; D002417:Cattle; D002455:Cell Division; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D005453:Fluorescence; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008027:Light; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D011073:Polyamines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000071228:Polyelectrolytes; D011108:Polymers / Q000737:chemistry*; D012965:Sodium Chloride; D013329:Structure-Activity Relationship; D014162:Transfection / Q000379:methods*
D000838:Anions; D004247:DNA; D008156:Luciferases; D011073:Polyamines; D000071228:Polyelectrolytes; D011108:Polymers; D012965:Sodium Chloride; C427203:calf thymus DNA