Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands; Groningen Research Institute of Pharmacy, Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands.
Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
J Control Release. 2019 Feb 28;296:250-257. doi: 10.1016/j.jconrel.2018.12.039. Epub 2019 Jan 22.
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 PDGFβ-receptor, using the drug carrier pPB-MSA. This carrier consists of mouse serum albumin (MSA) covalently coupled to several PDGFβR-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 PDGFβ-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.
肝星状细胞 (HSCs) 中的 Rho 激酶活性与这些细胞的活化、转化和收缩有关，导致细胞外基质产生和肝硬化时的门脉高压。抑制 Rho 激酶活性可以减少这些活性，但也可能导致副作用，例如全身性低血压。通过将 Rho 激酶抑制剂靶向递送到效应细胞，可以避免这种情况。因此，我们使用药物载体 pPB-MSA 将 Rho 激酶抑制剂 Y27632 靶向递送到肝纤维化的关键致病细胞，即肌成纤维细胞，包括高度表达 PDGFβ 受体的活化 HSCs。该载体由与几个 PDGFβR 识别部分（pPB）共价偶联的鼠血清白蛋白（MSA）组成。我们旨在通过将 pPB-MSA-Y27632 包封在可生物降解的聚合物微球中，创建这样的靶向构建物的延长释放系统，从而减少短暂的峰值浓度和频繁给药的需求。首先，我们在使用在胶原凝胶上接种的 HSCs 的收缩测定中证实了 PDGFβ 受体靶向 Y27632 的体外扩张作用。随后，我们在 Mdr2-/- 小鼠进行性胆汁性肝纤维化模型中证明了 pPB-MSA-Y27632 载药微球的体内抗纤维化功效。单次皮下微球给药后，一周后进行器官收获，明显减轻了肝纤维化的进展，并显著抑制了纤维化相关基因的表达，如几种胶原、成纤维细胞因子和基质金属蛋白酶。总之，我们证明了聚合物微球适合作为药物递送系统，用于持续系统递送具有抗纤维化潜力的靶向蛋白构建体，如 pPB-MSA-Y27632。该制剂似乎适合持续治疗肝纤维化和其他可能的慢性疾病。
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