Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Department of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland.
Eur J Pharm Biopharm. 2017 Oct;119:322-332. doi: 10.1016/j.ejpb.2017.07.002. Epub 2017 Jul 16.
Nanoparticles, such as polymersomes, can be directed to the hepatic asialoglycoprotein receptor to achieve targeted drug delivery. In this study, we prepared asialofetuin conjugated polymersomes based on the amphiphilic di-block copolymer poly(dimethylsiloxane)-b-poly(2-methyloxazoline) (PDMS-b-PMOXA). They had an average diameter of 150nm and formed monodisperse vesicles. Drug encapsulation and sustained release was monitored using the hydrophilic model compound carboxyfluorescein. Asialoglycoprotein receptor specific uptake by HepG2 cells in vitro was energy dependent and could be competitively inhibited by the free targeting ligand. Mechanistic uptake studies revealed intracellular trafficking of asialofetuin conjugated polymersomes from early endosomes and to the lysosomal compartment. Polymersomes showed no toxicity in the MTT assay up to concentrations of 500μg/mL. In addition, acute toxicity and tolerability of our PDMS-b-PMOXA polymersome formulations was assessed in vivo using zebrafish embryos as a vertebrate screening model. In conclusion, a hepatocyte specific drug delivery system was designed, which is safe and biocompatible and which can be used to implement liver-specific targeting strategies.
纳米粒子，如聚合物囊泡，可以被导向到肝唾液酸糖蛋白受体以实现靶向药物传递。在这项研究中，我们基于两亲性嵌段共聚物聚（二甲基硅氧烷）-b-聚（2-甲基恶唑啉）（PDMS-b-PMOXA）制备了去唾液酸胎球蛋白偶联的聚合物囊泡。它们的平均直径为 150nm 并形成单分散囊泡。使用亲水性模型化合物羧基荧光素监测药物包封和持续释放。体外 HepG2 细胞中去唾液酸糖蛋白受体的特异性摄取是能量依赖性的，并且可以被游离靶向配体竞争性抑制。机制摄取研究表明，去唾液酸胎球蛋白偶联的聚合物囊泡从早期内体到溶酶体区室进行细胞内转运。聚合物囊泡在 MTT 测定中直至 500μg/mL 的浓度下均无毒性。此外，还使用斑马鱼胚胎作为脊椎动物筛选模型在体内评估了我们的 PDMS-b-PMOXA 聚合物囊泡制剂的急性毒性和耐受性。总之，设计了一种肝特异性药物传递系统，该系统安全且生物相容，可用于实施肝特异性靶向策略。
