Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, PR China.
Biomaterials. 2013 Jan;34(1):306-19. doi: 10.1016/j.biomaterials.2012.09.058. Epub 2012 Oct 13.
High density lipoproteins (HDL) have been successfully reconstructed to deliver a large number of lipophilic drugs. Here, discoidal and spherical recombinant HDL loaded with cardiovascular drug tanshinone IIA (TA) were constructed (TA-d-rHDL and TA-s-rHDL), respectively. And next their in vitro physiochemical and biomimetic properties were characterized. Furthermore, pharmacokinetics, atherosclerotic lesions targeting effects and antiatherogenic efficacies were elaborately performed and compared in atherosclerotic New Zealand White (NZW) rabbits. In vitro characterizations results showed that both TA-d-rHDL and TA-s-rHDL had nano-size diameter, high entrapment efficiency (EE) and drug-loading capacity (DL). Additionally, similar to their native counterparts, TA-d-rHDL maintained remodeling behaviors induced by lecithin cholesterol acyltransferase (LCAT), and TA leaked during remodeling behaviors. Pharmacokinetic studies manifested that both TA-d-rHDL and TA-s-rHDL markedly improved pharmacokinetic behaviors of TA in vivo. Ex vivo imaging demonstrated that both d-rHDL and s-rHDL bound more avidly to atherosclerotic lesions than to normal vessel walls, and s-rHDL had better targeting effect than d-rHDL. Pharmacodynamic tests illustrated that both TA-d-rHDL and TA-s-rHDL had much stronger antiatherogenic efficacies than conventional TA nanostructured lipid carriers (TA-NLC), TA liposomes (TA-L) and commercially available preparation Sulfotanshinone Sodium Injection (SSI). Moreover, TA-s-rHDL had more potent antiatherogenic efficacies than TA-d-rHDL. Collectively our studies indicated that rHDL could be exploited as potential delivery vehicles of TA targeting atherosclerotic lesions as well as synergistically improving efficacies, especially for s-rHDL.
高密度脂蛋白（HDL）已成功重建，以递送大量亲脂性药物。在这里，分别构建了载有心血管药物丹参酮 IIA（TA）的盘状和球状重组 HDL（TA-d-rHDL 和 TA-s-rHDL）。并对其体外理化性质和仿生特性进行了表征。此外，在动脉粥样硬化新西兰白兔（NZW）中详细研究并比较了它们的药代动力学、动脉粥样硬化病变靶向作用和抗动脉粥样硬化功效。体外特性研究结果表明，TA-d-rHDL 和 TA-s-rHDL 均具有纳米级粒径、高包封效率（EE）和载药量（DL）。此外，与天然 HDL 类似，TA-d-rHDL 保持了卵磷脂胆固醇酰基转移酶（LCAT）诱导的重塑行为，并且 TA 在重塑过程中泄漏。药代动力学研究表明，TA-d-rHDL 和 TA-s-rHDL 均显著改善了 TA 的体内药代动力学行为。离体成像研究表明，d-rHDL 和 s-rHDL 均比正常血管壁更强烈地结合动脉粥样硬化病变，并且 s-rHDL 比 d-rHDL 具有更好的靶向作用。药效学试验表明，TA-d-rHDL 和 TA-s-rHDL 均比常规 TA 纳米结构脂质载体（TA-NLC）、TA 脂质体（TA-L）和市售制剂丹参酮磺酸钠注射液（SSI）具有更强的抗动脉粥样硬化功效。此外，TA-s-rHDL 比 TA-d-rHDL 具有更强的抗动脉粥样硬化功效。总之，我们的研究表明，rHDL 可以作为靶向动脉粥样硬化病变的 TA 的潜在递送载体，以及协同提高功效，特别是 s-rHDL。
