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

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.

Efficient drug and gene delivery to liver fibrosis: rationale, recent advances, and perspectives

“…Synthesized VA-PEG-PEI poly( N -( N ′, N ′-diisopropylamino ethyl)- co -benzyl amino)aspartamide (T-PBP) and its assembly into SPIO-decorated cationic micelle was able to transport the miRNA-29b and miRNA-122 to HSC in a magnetic resonance imaging-visible manner. Moreover, this combination improved liver function and alleviated hepatic fibrosis, whereas the non-targeting combination treatment showed almost no effect 120 .…”

“…Down regulation of Pdgfrb expression caused suppression of activated HSCs and improvement of liver function 97 . The effectiveness of siRNAs among the various gene therapies has been revealed by different researcher and the prominent studies are summarized in Table 3 76 , 80 , 91 , 93 , 96 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 .…”

Bimodal Imaging‐Visible Nanomedicine Integrating CXCR4 and VEGFa Genes Directs Synergistic Reendothelialization of Endothelial Progenitor Cells

“…The detailed acquisition parameters were described previously. [ 57 ] All experiments were conducted in triplicate.…”

Recent Advances in Nanomedicine for the Diagnosis and Therapy of Liver Fibrosis

“…A pH-sensitive and VA-conjugated copolymer cationic micelle that was coupled with a superparamagnetic iron oxide nanoparticle could transport miRNA-29b and miRNA-112 to HSCs in an MRI-visible manner. Synergistic antifibrotic therapeutic efficacy was achieved by downregulating the expression of fibrosis-related genes, including collagen Iα1, α-SMA, and a tissue inhibitor of MMP1 ( Figure 5 ) [ 109 ].…”

“…Abbreviations: COL1A1, collagen type I alpha 1 protein; TIMP1, tissue inhibitor of metalloproteinase 1; SPIO, superparamagnetic iron oxide. Reproduced with permission from [ 109 ]. Copyright John Wiley and Sons, 2019.…”