Self-Assembly of Polyamine−Poly(ethylene glycol) Copolymers with Phosphorothioate Oligonucleotides

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Abstract
The cationic copolymers for DNA delivery were synthesized by conjugating poly(ethylene glycol) (PEG) and polyamines: polyspermine (PSP) and polyethyleneimine (PEI). These molecules spontaneously form electrostatic complexes with a model 24-mer phoshorothioate oligonucleotide, T24 (PS−ODN). The copolymer complexes are water soluble. This is a marked contrast with the complexes formed by nonmodified PSP and PEI, which immediately precipitate out of solution. The potentiometric titration study suggests that the amino groups of the copolymers form a cooperative system of salt bonds with the thiophosphate groups of the PS−ODN. The PEG−PEI complexes are stable at physiological pH and ionic strengths. The PEG−PSP complexes are less stable in the presence of the low molecular mass electrolytes compared to the PEG−PEI complexes. The dynamic light scattering and transmission electron microscopy demonstrate that the complex particles are smallca. 12 nm for PEG−PSP and ca. 32 nm for PEG−PEI. They can be lyophilized and redissolved or stored in solution for up to several months without changing size. The study suggests that as a result of formulation with the PEG−PEI the interactions of PS−ODNs with serum proteins (using the example of bovine serum albumin) are decreased and PS−ODN is protected against nuclease degradation. The simplicity of preparation and long shelf life make these systems attractive as potential pharmaceutical formulations for oligonucleotides.