The antifibrotic potential of a sustained release formulation of a PDGF beta-receptor targeted rho kinase inhibitor

Autor: Klaas Poelstra, Matthias H. M. Klose, Angela Casini, F. van Dijk, Leonie Beljaars, Niels J. Sijbrandi, Samuel M. Meier-Menches, Eduard Post, Peter Olinga, Detlef Schuppan, Yong Ook Kim, Peter Horvatovich, Wouter L. J. Hinrichs, Naomi Teekamp, Johan Zuidema, Rob Steendam, Hendrik W. Frijlink
Přispěvatelé: Nanomedicine & Drug Targeting, Pharmaceutical Technology and Biopharmacy, Analytical Biochemistry, Medicinal Chemistry and Bioanalysis (MCB), Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Nanotechnology and Biophysics in Medicine (NANOBIOMED), Groningen Institute for Organ Transplantation (GIOT)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Liver Cirrhosis
Drug targeting
Pyridines
Polymeric microspheres
Pharmaceutical Science
02 engineering and technology
Pharmacology
chemistry.chemical_compound
Y-27632
Fibrosis
Controlled release
Rho-associated protein kinase
Mice
Knockout
0303 health sciences
Drug Carriers
rho-Associated Kinases
Chemistry
CIRRHOTIC RATS
021001 nanoscience & nanotechnology
Microspheres
Drug delivery
Female
0210 nano-technology
Drug carrier
ATP Binding Cassette Transporter
Subfamily B
SIGNALING CONTRIBUTES
Liver fibrosis
Biologicals
HEPATIC STELLATE CELLS
Cell Line
MECHANISMS
Receptor
Platelet-Derived Growth Factor beta
03 medical and health sciences
DELIVERY
ROCK INHIBITOR
medicine
Animals
Humans
Protein Kinase Inhibitors
030304 developmental biology
Protein delivery
PORTAL PRESSURE
medicine.disease
Amides
Targeted drug delivery
Rho kinase inhibitor
Delayed-Action Preparations
Hepatic stellate cell
VASODILATION
Zdroj: Journal of Controlled Release, 296, 250-257. Elsevier Bedrijfsinformatie b.v.
ISSN: 1873-4995
0168-3659
Popis: Rho kinase activity in hepatic stellate cells (HSCs) is associated with activation, transformation and contraction of these cells, leading to extracellular matrix production and portal hypertension in liver cirrhosis. Inhibition of rho kinase activity can reduce these activities, but may also lead to side effects, for instance systemic hypotension. This can be circumvented by liver-specific delivery of a rho kinase inhibitor to effector cells. Therefore, we targeted the rho kinase inhibitor Y27632 to the key pathogenic cells in liver fibrosis, i.e. myofibroblasts including activated HSCs that highly express the PDGF beta-receptor, using the drug carrier pPB-MSA. This carrier consists of mouse serum albumin (MSA) covalently coupled to several PDGF beta-recognizing moieties (pPB). We aimed to create a prolonged release system of such a targeted construct, by encapsulating pPB-MSA-Y27632 in biodegradable polymeric microspheres, thereby reducing short-lasting peak concentrations and the need for frequent administrations. Firstly, we confirmed the vasodilating potency of PDGF beta-receptor targeted Y27632 in vitro in a contraction assay using HSCs seeded on a collagen gel. We subsequently demonstrated the in vivo antifibrotic efficacy of pPB-MSA-Y27632-loaded microspheres in the Mdr2 - / - mouse model of progressive biliary liver fibrosis. A single subcutaneous microsphere administration followed by organ harvest one week later clearly attenuated liver fibrosis progression and significantly suppressed the expression of fibrosis related genes, such as several collagens, profibrotic cytokines and matrix metalloproteinases. In conclusion, we demonstrate that polymeric microspheres are suitable as drug delivery system for the sustained systemic delivery of targeted protein constructs with antifibrotic potential, such as pPB-MSA-Y27632. This formulation appears suitable for the sustained treatment of liver fibrosis and possibly other chronic diseases.
Databáze: OpenAIRE
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