Characterization of polyion complex micelles designed to address the challenges of oligonucleotide delivery.
OBJECTIVE
To optimize oligonucleotide (ODN)-based polyion complex micelles (PICMs) by studying the effects of polymer composition and length on their properties.


METHODS
Atom transfer radical polymerization was used to synthesize copolymers with increasing hydrophilic nonionic and cationic block lengths. PICMs were prepared by mixing the copolymers and ODN at various nitrogen-to-phosphate (N/P) ratios and characterized by gel electrophoresis and dynamic light scattering. The stability of the complexes towards dissociation was tested using a competitive assay with heparin. Finally, protection of the incorporated ODN against DNAse I degradation was evaluated.


RESULTS
A library of copolymers composed of poly(ethylene glycol) (PEG) and poly(aminoethyl methacrylate) (PAEMA) and/or poly((dimethylamino)ethylmethacrylate) (PDMAEMA) was synthesized. All polymers efficiently interacted with the ODN at N/P ratios approaching 1.5. Narrowly distributed but easily dissociable PICMs were obtained using PEG 5000 and short DMAEMA chains. Shortening the PEG block to 2000, increasing the number of cationic units and using AEMA produced more stable complexes but at the cost of colloidal properties. All polymers were able to protect the ODN from nuclease degradation.


CONCLUSIONS
PEG 3000-based PICMs possess good colloidal properties, intermediate stability towards dissociation and adjustable buffering capacity, making them potentially useful for the delivery of nucleic acid drugs.
Dufresne
Marie-Hélène
MH
Faculty of Pharmacy, University of Montreal, P.O. Box 6128, Downtown Station, Montreal, Quebec, H3C 3J7, Canada.
Elsabahy
Mahmoud
M
Leroux
Jean-Christophe
JC
D002021:Buffers; D003850:Deoxyribonuclease I / Q000378:metabolism; D018014:Gene Transfer Techniques; D006493:Heparin / Q000737:chemistry; D008689:Methacrylates / Q000138:chemical synthesis*; D008823:Micelles; D008970:Molecular Weight; D009584:Nitrogen / Q000737:chemistry; D009757:Nylons / Q000138:chemical synthesis*; D010710:Phosphates / Q000737:chemistry; D054735:Phosphorothioate Oligonucleotides / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000138:chemical synthesis*
D002021:Buffers; D008689:Methacrylates; D008823:Micelles; D009757:Nylons; D010710:Phosphates; D054735:Phosphorothioate Oligonucleotides; C407037:poly(2-(dimethylamino)ethyl methacrylate); D011092:Polyethylene Glycols; C072703:2-aminoethylmethacrylate; D006493:Heparin; D003850:Deoxyribonuclease I; D009584:Nitrogen