Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid.
Nanomedicine
; 13(7): 2329-2339, 2017 Oct.
Article
in En
| MEDLINE
| ID: mdl-28712920
ABSTRACT
Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A2 (TXA2), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Polyethyleneimine
/
RNA, Small Interfering
/
Cyclooxygenase 1
/
RNAi Therapeutics
/
Hyaluronic Acid
/
Hypertension, Portal
Limits:
Animals
Language:
En
Journal:
Nanomedicine
Journal subject:
BIOTECNOLOGIA
Year:
2017
Type:
Article