title: Compositional regulation of poly(lysine-g-(lactide-b-ethylene glycol))-DNA complexation and stability.
abstract: The search for an effective nonviral gene therapy vector has revealed several significant hurdles, such as transient expression and cytotoxicity, that impede the success of these systems. A terpolymer of poly(lysine-g-(lactide-b-ethylene glycol)) [pK-g-p(LL-b-EG)] has been developed, which is capable of stably packaging DNA with significantly less polycation than unmodified polylysine (pK) systems. A comparison of unmodified pK (DP=14, M(w)=2930) to pK grafted with p(LL-b-EG) (M(w tot)=7500) showed that the minimum amine/phosphate ratio (N:P(min)) needed for complete DNA condensation was reduced by 50%. However, when the molecular weight of pK was reduced (DP=4, M(w)=838), there was evidence of terpolymer interference with DNA condensation. Increasing the number of grafted p(LL-b-EG) chains produced a similar result of incomplete DNA condensation. All terpolymer formulations produced complexes with DNA that had greater resistance to salt-induced dissociation and short-term exchange with excess DNA. Terpolymer-DNA complexes exhibited approximately zero-order plasmid release profiles over a period of 6 weeks. The rate of release was dependent on the complex N:P ratio as well as the molecular weights of pLL and pK. The ability to use terpolymer composition to control complex stability and controlled release can provide a means for system optimization for sustained expression profiles of exogenous DNA.
authors.affiliation: Departments of Bioengineering and Materials Science and Engineering, University of California at Berkeley, 370 Hearst Memorial Mining Building, Berkeley, CA 94720-1760, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Park
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Healy
mesh_terms: D004247:DNA / Q000737:chemistry*; D004269:DNA, Bacterial / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000737:chemistry; D004355:Drug Stability; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D008970:Molecular Weight; D010957:Plasmids / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D004269:DNA, Bacterial; D003692:Delayed-Action Preparations; C478636:poly(lysine-g-(lactide-b-ethylene glycol)); D011092:Polyethylene Glycols; D004247:DNA