School of Pharmacy, Fudan University, Shanghai, China.
J Drug Target. 2013 May;21(4):367-74. doi: 10.3109/1061186X.2012.757769. Epub 2013 Apr 19.
High-density lipoprotein (HDL) particles can deliver cholesterol from peripheral tissues to the liver through apolipoprotein A1 (Apo A1), which specifically binds to the scavenger receptor class B type 1 (SR-B1) receptor on the surface of hepatocytes. Therefore, ApoA1 can be potentially used to target drugs to the liver. In this study, we successfully loaded doxorubicin hydrochloride (Dox or Dox-HCl), which is a hydrophilic drug used in a wide variety of clinical applications, into the core of reconstituted HDL (rHDL prepared by apoAI and egg phospholipids) to form a doxorubicin-HDL complex (rHDL-Dox). The MTT assays showed that rHDL-Dox particles also had higher cytotoxicity against several cells lines compared to free drug or Dox encapsulated into liposomes. A cellular uptake assay demonstrated that rHDL-Dox had higher absorption in SR-BI receptor positive liver cells. Importantly, in vivo experiments showed that rHDL-Dox can reduce tumor growth more effectively than liposomes. In addition, an in vitro hemolysis assay showed that rHDL-Dox caused only limited hemolysis in the case of high doses. Taken together, our findings indicate that rHDL is a safe and effective drug delivery system for targeting liver.
高密度脂蛋白 (HDL) 颗粒可通过载脂蛋白 A1（Apo A1）将胆固醇从外周组织转运至肝脏，Apo A1 可特异性结合到肝细胞表面的清道夫受体 B 类 1 型（SR-B1）受体。因此，ApoA1 可用于将药物靶向递送至肝脏。在本研究中，我们成功地将亲水性药物盐酸多柔比星（Dox 或 Dox-HCl）加载到由载脂蛋白 AI 和卵磷酯制备的重组高密度脂蛋白（rHDL）核心中，形成多柔比星-HDL 复合物（rHDL-Dox）。MTT 测定表明，与游离药物或包封在脂质体中的 Dox 相比，rHDL-Dox 颗粒对几种细胞系也具有更高的细胞毒性。细胞摄取测定表明，rHDL-Dox 在 SR-BI 受体阳性的肝细胞中具有更高的吸收。重要的是，体内实验表明，rHDL-Dox 比脂质体更能有效地抑制肿瘤生长。此外，体外溶血试验表明，rHDL-Dox 在高剂量时仅引起有限的溶血。总之，我们的研究结果表明，rHDL 是一种安全有效的肝靶向药物递送系统。
