Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands.
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands; Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, Groningen, The Netherlands.
Int J Pharm. 2017 Dec 20;534(1-2):229-236. doi: 10.1016/j.ijpharm.2017.09.072. Epub 2017 Oct 14.
Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFβR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFβR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFβR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA.
可注射持续释放药物输送系统是静脉内输送治疗性蛋白质的一种有吸引力的替代方法。特别是对于纤维化等慢性疾病，这种方法可以通过减少给药频率来改善治疗效果，同时避免血浆水平的大幅波动。在纤维化组织中，血小板衍生生长因子受体β（PDGFβR）高度上调，这为药物的靶向递药提供了一个靶点。我们的目的是开发一种可注射的持续释放制剂，用于皮下递送至 PDGFβR 靶向药物载体蛋白 pPB-HSA，该蛋白由多个与 PDGFβR 识别的部分（pPB）与人血清白蛋白（HSA）相连。我们使用不同溶胀度的可生物降解多嵌段共聚物混合物，通过油包水双乳液蒸发工艺从微球中生产模型蛋白 HSA 来优化释放速率。含有 pPB-HSA 的优化制剂在体外 14 天内完全释放。在皮下给予患有肾纤维化的小鼠后，pPB-HSA 从微球中释放出来，并在给药后至少 7 天分布到血浆中。此外，我们证明了 pPB-HSA 在纤维化肾脏中的积累增加。总的来说，我们表明，皮下给予的聚合物微球为 pPB-HSA 等蛋白质的系统控释提供了一种合适的持续释放药物输送系统。
