Jiaying University, Meizhou 514031, China; Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China; Guangdong Provincial Key Laboratory of Conservation and Precision Utilization of Characteristic Agricultural Resources in Mountainous Areas, JiaYing University, Meizhou, Guangdong 514015, China.
Institute of Hakka Medicinal Bio-resources, Medical College, Jiaying University, Meizhou 514031, China.
Int J Pharm. 2022 Aug 25;624:121967. doi: 10.1016/j.ijpharm.2022.121967. Epub 2022 Jun 28.
In this study, we explored the effect of the hydrophile-lipophile balance (HLB) in the linker unit of Galactose (Gal)/N-acetylgalactosamine (GalNAc) ligands on their affinity toward asialoglycoprotein receptors (ASGPRs). Two Gal/GalNAc ligands with lipophilic linkers-{(5-cholesten-3b-ol)[(2-acetamido-2-deoxy-d-galactopyranose-6-o)sebacate]} (CHS-6-GalNAc) and {(5-cholesten-3b-ol)[(d-galactopyranose-6-o)sebacate]} (CHS-6-Gal)-and two with hydrophilic linkers-{(5-cholesten-yl)[(4-O-b-D-galactopyranosyl)-D-glucitol-6-yl]sebacate} (CHS-1-Gal) and {(5-cholesten-3a-ol)[(2-acetamido-2-deoxy-d-galactopyranose-6-o)3,6-dioxa-octanedioate]} (CHS-PEG-6-GalNAc)-were synthesized by enzymatic catalysis. Compared with unmodified liposomes, all Gal/GalNAc ligand-modified liposomes showed higher efficiency toward the hepatocyte target as evaluated by weighted-average overall drug-targeting efficiency (Te*) in vivo and HepG2 cell uptake efficiency in vitro. The ligands containing linkers with high HLB values (i.e., CHS-PEG-6-GalNAc and CHS-1-Gal) exhibited higher ASGPR affinity than those containing linkers with low HLB values (i.e., CHS-6-GalNAc and CHS-6-Gal). We used molecular-dynamics (MD) simulations to investigate the structure-activity relationship between the HLB value of the linker in a ligand and ASGPR affinity. MD simulation results indicated that a Gal/GalNAc ligand with a more hydrophilic linker (i.e., higher HLB value) unit tended to have a higher solvent-accessible surface area (SASA), leading to lower steric hindrance for effective ASGPR recognition. The results of this study will provide an improved design for Gal/GalNAc ligand-based surface-modified liposomes with high ASGPR affinity.
在这项研究中，我们探讨了亲水亲油平衡（HLB）在半乳糖（Gal）/N-乙酰半乳糖胺（GalNAc）配体连接单元中的作用对其与去唾液酸糖蛋白受体（ASGPR）亲和力的影响。两种带有疏水性连接体的 Gal/GalNAc 配体-{(5-胆甾烯-3b-醇)[（2-乙酰氨基-2-脱氧-d-半乳糖吡喃糖-6-o）癸酸酯]}（CHS-6-GalNAc）和{(5-胆甾烯-3b-醇)[（d-半乳糖吡喃糖-6-o）癸酸酯]}（CHS-6-Gal）-和两种带有亲水性连接体的 Gal/GalNAc 配体-{(5-胆甾烯基)[（4-O-β-D-半乳糖吡喃糖基）-D-葡萄糖醇-6-yl]癸酸酯}（CHS-1-Gal）和{(5-胆甾烯-3a-醇)[（2-乙酰氨基-2-脱氧-d-半乳糖吡喃糖-6-o）3,6-二氧杂辛二酸酯]}（CHS-PEG-6-GalNAc）-是通过酶催化合成的。与未修饰的脂质体相比，所有 Gal/GalNAc 配体修饰的脂质体在体内通过加权平均总体药物靶向效率（Te*）和体外 HepG2 细胞摄取效率评估对肝细胞靶标具有更高的效率。含有高 HLB 值连接体的配体（即 CHS-PEG-6-GalNAc 和 CHS-1-Gal）比含有低 HLB 值连接体的配体（即 CHS-6-GalNAc 和 CHS-6-Gal）具有更高的 ASGPR 亲和力。我们使用分子动力学（MD）模拟来研究配体中连接体的 HLB 值与 ASGPR 亲和力之间的结构-活性关系。MD 模拟结果表明，具有更亲水连接体（即更高 HLB 值）单元的 Gal/GalNAc 配体往往具有更高的溶剂可及表面积（SASA），从而降低了有效 ASGPR 识别的空间位阻。这项研究的结果将为具有高 ASGPR 亲和力的 Gal/GalNAc 配体为基础的表面修饰脂质体提供更好的设计。
