6533b854fe1ef96bd12af420
RESEARCH PRODUCT
The antifibrotic potential of a sustained release formulation of a PDGF beta-receptor targeted rho kinase inhibitor
Klaas PoelstraMatthias H. M. KloseAngela CasiniF. Van DijkLeonie BeljaarsNiels J. SijbrandiSamuel M. Meier-menchesEduard PostPeter OlingaDetlef SchuppanYong Ook KimPeter HorvatovichWouter L. J. HinrichsNaomi TeekampJohan ZuidemaRob SteendamHendrik W. Frijlinksubject
Liver CirrhosisDrug targetingPyridinesPolymeric microspheresPharmaceutical Science02 engineering and technologyPharmacologychemistry.chemical_compoundY-27632FibrosisControlled releaseRho-associated protein kinaseMice Knockout0303 health sciencesDrug Carriersrho-Associated KinasesChemistryCIRRHOTIC RATS021001 nanoscience & nanotechnologyMicrospheresY-27632Drug deliveryFemale0210 nano-technologyDrug carrierATP Binding Cassette Transporter Subfamily BSIGNALING CONTRIBUTESLiver fibrosisBiologicalsHEPATIC STELLATE CELLSCell LineMECHANISMSReceptor Platelet-Derived Growth Factor beta03 medical and health sciencesDELIVERYROCK INHIBITORmedicineAnimalsHumansProtein Kinase Inhibitors030304 developmental biologyProtein deliveryPORTAL PRESSUREmedicine.diseaseAmidesTargeted drug deliveryRho kinase inhibitorDelayed-Action PreparationsHepatic stellate cellVASODILATIONdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-02-28 | Journal of Controlled Release |