Environment-Responsive Block Copolymer Micelles with a Disulfide Cross-Linked Core for Enhanced siRNA Delivery

被引：257

作者：

Matsumoto, Satoru ^{[1
]}

Christie, R. James ^{[1
]}

Nishiyama, Nobuhiro ^{[3
,5
]}

Miyata, Kanjiro ^{[2
,5
]}

Ishii, Atsushi ^{[1
,6
]}

Oba, Makoto ^{[4
]}

Koyama, Hiroyuki ^{[4
]}

Yamasaki, Yuichi ^{[1
,5
]}

Kataoka, Kazunori ^{[1
,2
,3
,5
,7
]}

机构：

[1] Univ Tokyo, Dept Mat Engn, Grad Sch Engn, Bunkyo Ku, Tokyo, Japan

[2] Univ Tokyo, Dept Bioengn, Grad Sch Engn, Bunkyo Ku, Tokyo, Japan

[3] Univ Tokyo, Grad Sch Med, Ctr Dis Biol & Integrat Med, Bunkyo Ku, Tokyo, Japan

[4] Univ Tokyo, Grad Sch Med, Dept Clin Vasc Regenerat, Bunkyo Ku, Tokyo, Japan

[5] Univ Tokyo, Ctr NanoBio Integrat, Bunkyo Ku, Tokyo, Japan

[6] NanoCarrier Co Ltd, Kashiwa, Chiba 2770882, Japan

[7] Japan Sci & Technol Agcy, CREST, Tokyo, Japan

来源：

BIOMACROMOLECULES | 2009年 / 10卷 / 01期

关键词：

POLYION COMPLEX MICELLES; IN-VIVO; SENSITIVE STABILIZATION; RNA INTERFERENCE; AQUEOUS-MEDIUM; GENE-TRANSFER; DNA; PHARMACOKINETICS; OLIGONUCLEOTIDE; GLUTATHIONE;

D O I：

10.1021/bm800985e

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 similar to 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.

引用

页码：119 / 127

页数：9

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