School of Pharmacy, Shenyang Pharmaceutical University, China.
School of Medical Devices, Shenyang Pharmaceutical University, China.
Colloids Surf B Biointerfaces. 2015 Jun 1;130:133-40. doi: 10.1016/j.colsurfb.2015.03.036. Epub 2015 Mar 25.
Pegylation method is widely used to prolong the blood circulation time of proteins and nanoparticles after intravenous administration, but the effect of surface poly (ethylene glycol) (PEG) chain length on oral absorption of the pegylated nanoparticles is poorly reported. The aim of our study was to investigate the influence of PEG corona chain length on membrane permeability and oral bioavailability of the amphiphilic pegylated prodrug-based nanomicelles, taking all trans-retinoic acid (ATRA) as a model drug. The amphiphilic ATRA-PEG conjugates were synthesized by esterification reaction between all trans-retinoic acid and mPEGs (mPEG500, mPEG1000, mPEG2000, and mPEG5000). The conjugates could self-assemble in aqueous medium to form nanomicelles by emulsion-solvent evaporation method. The resultant nanomicelles were in spherical shape with an average diameter of 13-20 nm. The drug loading efficiency of ATRA-PEG500, ATRA-PEG1000, ATRA-PEG2000, and ATRA-PEG5000 was about 38.4, 26.6, 13.1, and 5.68 wt%, respectively. With PEG chain length ranging from 500 to 5000, ATRA-PEG nanomicelles exhibited a bell shape of chemical stability in different pH buffers, intestinal homogenate and plasma. More importantly, they were all rapidly hydrolyzed into the parent drug in hepatic homogenate, with the half-time values being 0.3-0.4h. In comparison to ATRA solution and ATRA prodrug-based nanomicelles, ATRA-PEG1000 showed the highest intestinal permeability. After oral administration, ATRA-PEG2000 and ATRA-PEG5000 nanomicelles were not nearly absorbed, while the oral bioavailability of ATRA-PEG500 and ATRA-PEG1000 demonstrated about 1.2- and 2.0-fold higher than ATRA solution. Our results indicated that PEG1000 chain length of ATRA-PEG prodrug nanomicelles has the optimal oral bioavailability probably due to improved stability and balanced mucus penetration capability and cell binding, and that the PEG chain length on a surface of nanoparticles cannot exceed a key threshold with the purpose of enhancement in oral bioavailability.
聚乙二醇（PEG）化方法广泛用于延长蛋白质和纳米颗粒静脉给药后的血液循环时间，但表面聚乙二醇（PEG）链长对聚乙二醇化纳米颗粒口服吸收的影响报道甚少。我们的研究旨在研究 PEG 冠链长度对两亲性聚乙二醇化前药纳米胶束的膜通透性和口服生物利用度的影响，以全反式视黄酸（ATRA）为模型药物。通过全反式视黄酸与 mPEGs（mPEG500、mPEG1000、mPEG2000 和 mPEG5000）之间的酯化反应合成两亲性 ATRA-PEG 缀合物。缀合物可以在水介质中通过乳液溶剂蒸发法自组装形成纳米胶束。所得纳米胶束呈球形，平均直径为 13-20nm。ATRA-PEG500、ATRA-PEG1000、ATRA-PEG2000 和 ATRA-PEG5000 的载药量约为 38.4%、26.6%、13.1%和 5.68wt%。随着 PEG 链长从 500 到 5000，ATRA-PEG 纳米胶束在不同 pH 缓冲液、肠匀浆和血浆中表现出钟形的化学稳定性。更重要的是，它们在肝匀浆中均迅速水解为母体药物，半衰期值为 0.3-0.4h。与 ATRA 溶液和 ATRA 前药纳米胶束相比，ATRA-PEG1000 表现出最高的肠道通透性。口服给药后，ATRA-PEG2000 和 ATRA-PEG5000 纳米胶束几乎不被吸收，而 ATRA-PEG500 和 ATRA-PEG1000 的口服生物利用度分别约为 ATRA 溶液的 1.2 倍和 2.0 倍。我们的结果表明，ATRA-PEG 前药纳米胶束的 PEG1000 链长具有最佳的口服生物利用度，可能是由于改善了稳定性和平衡的粘液穿透能力和细胞结合能力，并且纳米颗粒表面的 PEG 链长不能超过关键阈值，以提高口服生物利用度。
