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

JOURNAL OF CONTROLLED RELEASE

卷:296

Article

van Dijk, F.^1,2  Teekamp, N.¹  Post, E.²  Schuppan, D.^3,4,5  Kim, Y. O.^3,4  Zuidema, J.⁶  Steendam, R.⁶  Klose, Matthias H. M.¹⁰  Meier-Menches, Samuel M.^7,10  Casini, A.⁷  Horvatovich, P. L.⁸  Sijbrandi, N. J.⁹  Frijlink, H. W.¹  Hinrichs, W. L. J.¹  Poelstra, K.²  Beljaars, L.²  Olinga, P.¹ 

[1] Univ Groningen, Groningen Res Inst Pharm, Dept Pharmaceut Technol & Biopharm, Groningen, Netherlands

[2] Univ Groningen, Groningen Res Inst Pharm, Dept Pharmacokinet Toxicol & Targeting, Groningen, Netherlands

[3] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Translat Immunol, Mainz, Germany

[4] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Res Ctr Immune Therapy, Mainz, Germany

[5] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Boston, MA USA

[6] InnoCore Pharmaceut, Groningen, Netherlands

[7] Cardiff Univ, Sch Chem, Pk Pl, Cardiff CF10 3AT, S Glam, Wales

[8] Univ Groningen, Dept Analyt Biochem, Groningen Res Inst Pharm, Groningen, Netherlands

[9] LinXis BV, Amsterdam, Netherlands

[10] Univ Vienna, Dept Analyt Chem, Waehringer Str 38, A-1090 Vienna, Austria

关键词: Controlled release;    Polymeric microspheres;    Protein delivery;    Drug targeting;    Biologicals;    Liver fibrosis;   

DOI  :  10.1016/j.jconrel.2018.12.039

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free