pH-labile PEGylation of siRNA-loaded lipid nanoparticle improves active targeting and gene silencing activity in hepatocytes

JOURNAL OF CONTROLLED RELEASE

卷:262

Article

Hashiba, Kazuki¹  Sato, Yusuke¹  Harashima, Hideyoshi¹ 

[1] Hokkaido Univ, Fac Pharmaceut Sci, Kita Ku, Kita 12 Nishi 6, Sapporo, Hokkaido 0600812, Japan

关键词: Maleic anhydride;    pH-labile;    PEGylation;    siRNA delivery;    Active target;    Lipid nanoparticles;   

DOI  :  10.1016/j.jconrel.2017.07.046

来源: Elsevier

【 摘 要 】

Lipid nanoparticles (LNPs) are one of the promising technologies for the in vivo delivery of short interfering RNA (siRNA). Modifying LNPs with polyethyleneglycol (PEG) is widely used to inhibit non-specific interactions with serum components in the blood stream, and is a useful strategy for maximizing the efficiency of active targeting. However, it is a widely accepted fact that PEGylation of the LNP surface strongly inhibits fusion between LNPs and endosomal membranes, resulting in poor cytosolic siRNA delivery, a process that is referred to as the 'PEGdilemma'. In the present study, in an attempt to overcome this problem, siRNA-loaded LNPs were modified with PEG through maleic anhydride, a pH-labile linkage. The in vitro, suppression of cationic charge, stealth function at physiological pH up to 1 h and the rapid desorption of PEG and restoration of fusogenic activity under slightly acidic conditions (within only 2 min) were achieved by PEG modification of the LNPs through maleic anhydride. In vivo, PEG modification through maleic anhydride resulted in a dramatic improvement in the targeting capability of the active targeting of ligand (N-acetyl-D-galactosamine)-modified LNPs to hepatocytes, with an approximately 14-fold increase in gene silencing activity in factor 7 model mice. Taken together, the maleic an-hydride-mediated pH-labile PEGylation of the active targeting LNPs is a useful strategy for achieving the specific and efficient delivery of siRNAs in vivo.

【 授权许可】

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