Research Article: Synergistic MicroRNA Therapy in Liver Fibrotic Rat Using MRI‐Visible Nanocarrier Targeting Hepatic Stellate Cells

Date Published: January 15, 2019

Publisher: John Wiley and Sons Inc.

Author(s): Jun Wu, Jinsheng Huang, Sichi Kuang, Jingbiao Chen, Xiaoxia Li, Bin Chen, Jin Wang, Du Cheng, Xintao Shuai.

http://doi.org/10.1002/advs.201801809

Abstract

Liver fibrosis, as one of the leading causes of liver‐related morbidity and mortality, has no Food and Drug Administration (FDA)‐approved antifibrotic therapy yet. Although microRNA‐29b (miRNA‐29b) and microRNA‐122 (miRNA‐122) have great potential in treating liver fibrosis via regulating profibrotic genes in hepatic stellate cells (HSCs), it is still a challenge to achieve a HSC‐targeted and meanwhile noninvasively trackable delivery of miRNAs in vivo. Herein, a pH‐sensitive and vitamin A (VA)‐conjugated copolymer VA–polyethylene glycol–polyethyleneimine–poly(N‐(N′,N′‐diisopropylaminoethyl)‐co‐benzylamino) aspartamide (T‐PBP) is synthesized and assembled into superparamagnetic iron oxide (SPIO)‐decorated cationic micelle for miRNA delivery. The T‐PBP micelle efficiently transports the miRNA‐29b and miRNA‐122 to HSC in a magnetic resonance imaging‐visible manner, resulting in a synergistic antifibrosis effect via downregulating the expression of fibrosis‐related genes, including collagen type I alpha 1, α‐smooth muscle actin, and tissue inhibitor of metalloproteinase 1. Consequently, the HSC‐targeted combination therapy with miRNA‐29b and miRNA‐122 demonstrates a prominent antifibrotic efficacy in terms of improving liver function and relieving hepatic fibrosis.

Partial Text

Liver fibrosis is a major liver disease characterized by accumulation of extracellular matrix (ECM) due to repeated liver injury,1, 2 and it may progress into liver cirrhosis, hepatic failure, and even hepatocellular carcinoma.3, 4 Although some antifibrotic agents, including anti‐inflammatory drugs (e.g., fresolimumab and pirfenidone), antioxidant agents (e.g., N‐acetylcysteine and diphenyleneiodonium), and antiviral drugs (e.g., entecavir and interferon γ), have been developed for clinical and preclinical trials, the limited efficacy and severe side effects are still main obstacles for their applications.5, 6, 7, 8, 9 Thus, an alternative strategy to treat hepatic fibrosis is in urgent need nowadays.

A vitamin A–terminated copolymer VA–PEG–bPEI–PAsp(DIP–BzA) was synthesized and self‐assembled to cationic nanoplex (T‐PBP). MRI contrast agent SPIO was encapsulated into the core of T‐PBP, and miRNAs were effectively complexed in the cationic bPEI interlayer. The vitamin A conjugation endowed the nanoplex with HSC‐targeting function, which appeared essential for realizing the synergistic effect of miRNA‐29b and miRNA‐122. In animal study, the HSC‐targeted combination treatment of miRNA‐29b and miRNA‐122 showed significant inhibitory effect on fibrosis‐related gene expressions, whereas the nontargeting combination treatment showed almost no effect. Consequently, the liver fibrosis was remarkably alleviated, and the liver functions were obviously recovered. This study showed the great potential of MRI‐visible nanocarrier targeting hepatic stellate cells to mediate highly effective anti–liver fibrosis treatment of miRNAs.

Materials: VA, RBP, MTT, α‐methoxy‐ε‐hydroxy‐poly(ethylene glycol) (Mn = 2 kDa), hyperbranched PEI (Mn = 1.8 kDa), N,N′‐carbonyldiimidazole, n‐butylamine, succinic anhydride, N,N‐diisopropylaminoethylamine, benzylamine, dicyclohexylcarbodiimide, and DAPI were purchased from Sigma‐Aldrich (St. Louis, USA). SPIO nanoparticles were synthesized using the solvothermal method.67

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1002/advs.201801809

 

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