Smart Multilayered Assembly for Biocompatible siRNA Delivery Featuring Dissolvable Silica, Endosome-Disrupting Polycation, and Detachable PEG
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- 作者：Tomoya Suma ; Kanjiro Miyata ; Yasutaka Anraku ; Sumiyo Watanabe ; R. James Christie ; Hiroyasu Takemoto ; Momoko Shioyama ; Noha Gouda ; Takehiko Ishii ; Nobuhiro Nishiyama ; Kazunori Kataoka
- 刊名：ACS Nano
- 出版年：2012
- 出版时间：August 28, 2012
- 年：2012
- 卷：6
- 期：8
- 页码：6693-6705
- 全文大小：667K
- 年卷期：v.6,no.8(August 28, 2012)
- ISSN：1936-086X
文摘
Multifunctional delivery systems of small interfering RNA (siRNA) are needed to overcome the intrinsic biological barriers toward efficient gene silencing in the cell cytoplasm. In this report, a smart multilayered assembly (SMA) was fabricated by a layer-by-layer method with polyionic materials. The SMA was designed to feature a siRNA-loaded core, a transiently core-stabilizing silica interlayer, an endosome-disrupting polycation interlayer, and a biocompatible poly(ethylene glycol) (PEG) shell with reductive environment-responsive detachability. The SMA was confirmed to be approximately 160 nm in size with narrow distribution and spherical morphology by DLS and TEM analyses. The PEG detachability of the SMA based on disulfide cleavage was also confirmed by the increase in both 味-potential and size due to the exposure of the polycation interlayer and the compromised colloidal stability. The silica interlayer rendered the SMA highly tolerant to dissociation induced by anionic lipids, while after 24 h dialysis siRNA release from the SMA was clearly observed, presumably due to gradual dissolution of the silica interlayer based on the equilibrium shift to silicate ions. The entrapment ratio of siRNA delivered by the SMA within the endosome was significantly lower than that by nondisulfide control (NDC) without PEG detachability, suggesting the improved endosomal escape of SMA with the exposed, endosome-disrupting interlayer after PEG detachment. SMAs induced significantly higher gene silencing efficiency in various cultured cells, compared to NDC, without associated cytotoxicity. The systemic administration of SMAs for subcutaneous tumor-bearing mice achieved significant endogenous gene silencing in tumor tissue without hematological toxicity.