Glutathione-sensitive stabilization of block copolymer micelles composed of antisense DNA and thiolated poly(ethylene glycol)-block-poly(L-lysine): a potential carrier for systemic delivery of antisense DNA.
Glutathione (GSH)-sensitive stabilization of polyion complex (PIC) micelles entrapping antisense oligonucleotide (ODN) was achieved by the reversible cross-linking of the core through disulfide bonds, aiming at the development of a novel DNA carrier system for antisense therapy following systemic administration. Thiolated poly(ethylene glycol)-block-poly(L-lysine) (PEG-thioPLL) and ODN spontaneously associated to form the PIC micelles with the core cross-linked through disulfide bonds. The diameters of the cross-linked micelles were similar to those of the non-cross-linked micelles and were determined to be about 40 nm by light scattering measurements. The micelles have sufficient colloidal stability due to the PEG shell surrounding the core of the polyion complex composed of PLL and ODN. The polyanion exchange studies suggested that the dissociation of the micelles was suppressed through the core cross-linking. The stability of the ODN in the core cross-linked micelles against nuclease was appreciably increased compared to that of free ODN and that in the micelles without cross-linking. On the other hand, the micelles dissociated to release ODN in the presence of GSH at a concentration comparable to the intracellular environment, featuring the potential ability of this system for intracellular ODN delivery.
Kakizawa
Y
Y
Department of Materials Science, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Harada
A
A
Kataoka
K
K
D003432:Cross-Linking Reagents / Q000737:chemistry; D016373:DNA, Antisense / Q000737:chemistry*; D003851:Deoxyribonucleases / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D004355:Drug Stability; D005978:Glutathione / Q000378:metabolism*; D008027:Light; D008823:Micelles; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D011107:Polylysine / Q000138:chemical synthesis / Q000737:chemistry*; D012542:Scattering, Radiation
D003432:Cross-Linking Reagents; D016373:DNA, Antisense; D004337:Drug Carriers; D008823:Micelles; C469930:thiolated poly(ethylene glycol)-block-poly(L-lysine); D011107:Polylysine; D011092:Polyethylene Glycols; D003851:Deoxyribonucleases; D005978:Glutathione