Engineered fibrotic liver-targeted truncated transforming growth factor ß receptor type II variant for superior anti-liver fibrosis therapy.
Arch Pharm Res
; 46(3): 177-191, 2023 Mar.
Article
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| MEDLINE
| ID: mdl-36905489
ABSTRACT
Truncated transforming growth factor ß receptor type II (tTßRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-ß1 by means of competing with wild type TßRII (wtTßRII). However, the widespread application of tTßRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTßRII variant Z-tTßRII by fusing the platelet-derived growth factor ß receptor (PDGFßR)-specific affibody ZPDGFßR to the N-terminus of tTßRII. The target protein Z-tTßRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTßRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFßR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTßRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-ß1/Smad pathway-related protein levels in TGF-ß1-stimiluated HSC-T6 cells. Furthermore, Z-tTßRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-ß1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTßRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTßRII or former variant BiPPB-tTßRII (PDGFßR-binding peptide BiPPB modified tTßRII). In addition, Z-tTßRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTßRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Factor de Crecimiento Transformador beta1
/
Cirrosis Hepática
Límite:
Animals
Idioma:
En
Revista:
Arch Pharm Res
Año:
2023
Tipo del documento:
Article