PURPOSE: 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.
PURPOSE: 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.
Authors: Mangesh C Deshpande; Martin C Garnett; M Vamvakaki; Lindsey Bailey; Steven P Armes; Snjezana Stolnik Journal: J Control Release Date: 2002-05-17 Impact factor: 9.776
Authors: P van de Wetering; E E Moret; N M Schuurmans-Nieuwenbroek; M J van Steenbergen; W E Hennink Journal: Bioconjug Chem Date: 1999 Jul-Aug Impact factor: 4.774
Authors: M A Wolfert; P R Dash; O Nazarova; D Oupicky; L W Seymour; S Smart; J Strohalm; K Ulbrich Journal: Bioconjug Chem Date: 1999 Nov-Dec Impact factor: 4.774