Targeted Delivery Of Oligonucleotides Into Hepatic Stellate Cells For Liver Fibrosis Therapy

Hepatic fibrosis is the liver disease characterized by excessive extracellar matrix deposition; there is currently no treatment available. As the development of hepatic fibrosis principally correlates with the overproduction of type I collagen by hepatic stellate cells (HSCs). However, all hepatic stellate cells (HSCs) are in hepatic sinusoidal, and account for about10%of the total number of liver cells, drugs can only be transferred into the liver cells and few can into the the hepatic stellate cell, so targeted delivery of drugs into hepatic stellate cell is rarely. We in this study aimed to develop a system to deliver the antisense oligodeoxynucleotide (ASO) against the main gene coding for type Ⅰ collagen (col1A1) specifically to HSCs. We conjugated small molecular weight polyetherimine (PEI) to retinol via an N,N’-carbonyldiimidazole (CDI)-activation method. Our hypothesis is that the electrostatic interaction between PEI and albumin in the blood circulation could harness the natural transporting capacity of albumin for liver-targeting delivery, and the specific interaction between retinol and Vitamin A receptor on HSCs could further enhance active targeting at the cellular level. In the murine liver fibrosis model induced by carbon tetrachloride (CCl4), the retinol-c-PEI/ASO complex was found to preferentially accumulate in the liver. Further evaluation on the therapeutic efficacy suggested that the expression of type Ⅰ collagen was markedly suppressed and liver fibrosis consequently ameliorated, in comparison with the naked ASO. All these findings suggest that this delivery system could provide a tool for antisense-based therapeutics against hepatic fibrosis.