Environment-responsive block copolymer micelles with a disulfide cross-linked core for enhanced siRNA delivery.
A core-shell-type polyion complex (PIC) micelle with a disulfide cross-linked core was prepared through the assembly of iminothiolane-modified poly(ethylene glycol)-block-poly(L-lysine) [PEG-b-(PLL-IM)] and siRNA at a characteristic optimum mixing ratio. The PIC micelles showed a spherical shape of approximately 60 nm in diameter with a narrow distribution. The micellar structure was maintained at physiological ionic strength but was disrupted under reductive conditions because of the cleavage of disulfide cross-links, which is desirable for siRNA release in the intracellular reductive environment. Importantly, environment-responsive PIC micelles achieved 100-fold higher siRNA transfection efficacy compared with non-cross-linked PICs prepared from PEG-b-poly(L-lysine), which were not stable at physiological ionic strength. PICs formed with PEG-b-(PLL-IM) at nonoptimum ratios did not assemble into micellar structure and did not achieve gene silencing following siRNA transfection. These findings show the feasibility of core cross-linked PIC micelles as carriers for therapeutic siRNA and show that stable micellar structure is critical for effective siRNA delivery into target cells.
Matsumoto
Satoru
S
Department of Materials Engineering, Graduate School of Engineering, Center for Disease Biology and Integrative Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Christie
R James
RJ
Nishiyama
Nobuhiro
N
Miyata
Kanjiro
K
Ishii
Atsushi
A
Oba
Makoto
M
Koyama
Hiroyuki
H
Yamasaki
Yuichi
Y
Kataoka
Kazunori
K
D003432:Cross-Linking Reagents / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D046911:Macromolecular Substances / Q000138:chemical synthesis / Q000737:chemistry; D008823:Micelles; D015394:Molecular Structure; D009994:Osmolar Concentration; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000378:metabolism*; D012965:Sodium Chloride / Q000737:chemistry; D013499:Surface Properties
D003432:Cross-Linking Reagents; D004220:Disulfides; D046911:Macromolecular Substances; D008823:Micelles; D034741:RNA, Small Interfering; C092361:poly(ethylene glycol) lysine copolymer; D011092:Polyethylene Glycols; D012965:Sodium Chloride; D008239:Lysine