Limits...
Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.

Schon HT, Bartneck M, Borkham-Kamphorst E, Nattermann J, Lammers T, Tacke F, Weiskirchen R - Front Pharmacol (2016)

Bottom Line: Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells.The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed.Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany.

ABSTRACT
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

No MeSH data available.


Related in: MedlinePlus

Cellular structures for targeting HSCs with nanoconjugate ligands. There are diverse different structures on HSCs, which have been used earlier for targeted delivery. The targeted structures (list on the left side), the corresponding ligands (right side list), and their location on HSCs are depicted in the scheme.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4764688&req=5

Figure 7: Cellular structures for targeting HSCs with nanoconjugate ligands. There are diverse different structures on HSCs, which have been used earlier for targeted delivery. The targeted structures (list on the left side), the corresponding ligands (right side list), and their location on HSCs are depicted in the scheme.

Mentions: The retinol binding protein receptor which is involved in storing retinol is another putative structure for targeting HSCs. Hence, lipid-encapsulated and retinol-decorated siRNA versus heat-shock protein 47, a collagen-specific chaperone, was shown to ameliorate fibrosis in diverse experimental mouse models (Sato et al., 2008). Nanoconjugate siRNA against TGF-β1 equipped with an N-acetylglucosamin targeting moiety intending to reach HSCs via desmin was reported to colocalize with HSCs and to reduce fibrosis (Kim et al., 2013). Due to the cytosolic presence of desmin, the conjugates may also enter the cells via alternative routes. Recently, siRNA directed against the procollagen α1(I) gene has been deployed using cationic nanoparticles, leading to an amelioration of fibrosis. However, despite the therapeutic success in preclinical studies, the delivery route was rather unspecific and probably occurs through endocytosis since none of the known cell-targeting motifs were used (Jiménez Calvente et al., 2015) (Figure 7).


Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.

Schon HT, Bartneck M, Borkham-Kamphorst E, Nattermann J, Lammers T, Tacke F, Weiskirchen R - Front Pharmacol (2016)

Cellular structures for targeting HSCs with nanoconjugate ligands. There are diverse different structures on HSCs, which have been used earlier for targeted delivery. The targeted structures (list on the left side), the corresponding ligands (right side list), and their location on HSCs are depicted in the scheme.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4764688&req=5

Figure 7: Cellular structures for targeting HSCs with nanoconjugate ligands. There are diverse different structures on HSCs, which have been used earlier for targeted delivery. The targeted structures (list on the left side), the corresponding ligands (right side list), and their location on HSCs are depicted in the scheme.
Mentions: The retinol binding protein receptor which is involved in storing retinol is another putative structure for targeting HSCs. Hence, lipid-encapsulated and retinol-decorated siRNA versus heat-shock protein 47, a collagen-specific chaperone, was shown to ameliorate fibrosis in diverse experimental mouse models (Sato et al., 2008). Nanoconjugate siRNA against TGF-β1 equipped with an N-acetylglucosamin targeting moiety intending to reach HSCs via desmin was reported to colocalize with HSCs and to reduce fibrosis (Kim et al., 2013). Due to the cytosolic presence of desmin, the conjugates may also enter the cells via alternative routes. Recently, siRNA directed against the procollagen α1(I) gene has been deployed using cationic nanoparticles, leading to an amelioration of fibrosis. However, despite the therapeutic success in preclinical studies, the delivery route was rather unspecific and probably occurs through endocytosis since none of the known cell-targeting motifs were used (Jiménez Calvente et al., 2015) (Figure 7).

Bottom Line: Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells.The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed.Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany.

ABSTRACT
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

No MeSH data available.


Related in: MedlinePlus