School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China; Municipal key laboratory of biopharmacetics, School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road, Shenyang 110016, China.
J Control Release. 2015 Jan 10;197:29-40. doi: 10.1016/j.jconrel.2014.10.024. Epub 2014 Nov 4.
Stealth active targeting nanoparticles (NPs) usually include two types of ligand sites: ligand anchored on distal ends of the polyethylene glycol (PEG) and ligand buried under pegylated layer. The latter typical case is hyaluronic acid (HA)-based NPs; however, there is little information available for the latter NPs about effect of the optimal density of surface PEG coating on the blood circulation time, cellular uptake and in vivo anticancer activity. Thus, in this study, in order to optimize the anticancer effects of HA-based NPs, we focus on how uncovalent pegylation degree modulates blood circulation time and cellular uptake of HA-based NPs. We firstly designed a new double-hydrophilic copolymer by conjugating HP-β-cyclodextrin with HA, and this carrier was further pegylated with adamantyl-peg (ADA-PEG) to form inclusion complex HA-HPCD/ADA-PEG, termed as HCPs. The supramolecular nanoassemblies were fabricated by host-guest and polar interactions between HCPs and doxorubicin (Dox), with vitamin E succinate (VES) being a nanobridge. Despite the active recognition between HA and CD44 receptor, the cellular uptake and targeting efficiency of HA-NPs decreased with the increasing peg density, demonstrating HA was partly buried by high density peg coating. However, the high density of peg coating was beneficial to long circulation time, tumor biodistribution and anticancer activity in vivo. NPs with 5% peg coating had the optimal cellular targeting efficiency in vitro and anticancer effects in vivo. The findings suggest that balancing long circulation property and cellular uptake is important to achieve the optimal antitumor efficacy for pegylated HA-based NPs, and that PEG coating densities cannot be extended beyond a certain density for shielding effect without compromising the efficacy of hyaluronic acid targeted delivery.
隐形主动靶向纳米粒子 (NPs) 通常包括两种配体结合位点：结合在聚乙二醇 (PEG) 远端的配体和埋在 PEG 层下的配体。后一种典型情况是基于透明质酸 (HA) 的 NPs；然而，对于后者 NPs，关于表面 PEG 涂层的最佳密度对血液循环时间、细胞摄取和体内抗癌活性的影响的信息很少。因此，在这项研究中，为了优化基于 HA 的 NPs 的抗癌效果，我们专注于非共价 PEG 化程度如何调节基于 HA 的 NPs 的血液循环时间和细胞摄取。我们首先通过将 HP-β-环糊精与 HA 偶联设计了一种新的双亲性共聚物，然后用金刚烷-PEG（ADA-PEG）对其进行 PEG 化，形成包含复合物 HA-HPCD/ADA-PEG，称为 HCPs。超分子纳米组装体通过 HCPs 与阿霉素 (Dox) 之间的主体-客体和极性相互作用以及维生素 E 琥珀酸酯 (VES) 作为纳米桥来构建。尽管 HA 与 CD44 受体之间存在主动识别，但随着 peg 密度的增加，HA-NPs 的细胞摄取和靶向效率降低，表明 HA 部分被高密度 peg 涂层掩埋。然而，高密度 peg 涂层有利于长循环时间、肿瘤生物分布和体内抗癌活性。具有 5% peg 涂层的 NPs 具有最佳的体外细胞靶向效率和体内抗癌效果。研究结果表明，平衡长循环特性和细胞摄取对于实现基于 PEG 的 HA 的最佳抗肿瘤疗效非常重要，并且在不影响透明质酸靶向递送效果的情况下，PEG 涂层密度不能超过一定密度以实现屏蔽效果。
