College of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
Department of Applied Chemistry, Yuncheng University, Yuncheng, 044000, Shanxi, China.
AAPS PharmSciTech. 2020 Mar 17;21(3):106. doi: 10.1208/s12249-020-1640-4.
To investigate the effect of polyethylene glycol (PEG) molecular weights on circulation time of PEGylated emulsions and the second injection of injected PEGylated emulsions, we studied the effect of molecular weights on the pharmacokinetic behavior of PEG-DSPE (modified emulsions with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethyleneglycol)]) and PEG-CHMC (modified emulsions with poly(ethyleneglycol)-cholesteryl carbonate) emulsions in beagle dogs. The "accelerated blood clearance" (ABC) phenomenon was induced. Through this study, the contribution of PEG molecular weights on the ABC phenomenon was further clarified, and the results provided guidance for lessening or eliminating the ABC phenomenon. We injected different PEG-modified emulsions with 10% PEG-modified density into beagle dogs at 2 μmol phospholipids kg and the blood samples were drawn after 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 60 min, 120 min, 240 min, 360 min, 600 min, and 24 h. Then, concentrations of the drug were assayed using high-performance liquid chromatography (HPLC). The results showed that the circulation times of PEG-DSPE-modified emulsions were significantly different because of the difference in molecular weights, whereas those of the PEG-CHMC modified emulsions were not. The spatial conformation of PEG with small molecular weights (PEG400, PEG600, and PEG800) was more likely to induce a strong ABC phenomenon. The results of our work suggest the interaction of circulation time and PEG molecular weights on the ABC phenomenon, implying that the spatial conformation of PEG has advantages that alleviate the ABC phenomenon. Importantly, the results have implications for the choice of molecular weights of PEG for PEGylated formulations.
为了研究聚乙二醇（PEG）分子量对 PEG 化乳剂循环时间和二次注射 PEG 化乳剂的影响，我们研究了分子量对 PEG-DSPE（用 1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-n-[甲氧基（聚乙二醇）]修饰的乳剂）和 PEG-CHMC（用聚（乙二醇）-胆固醇碳酸酯修饰的乳剂）在比格犬体内的药代动力学行为的影响。诱导了“加速血液清除”（ABC）现象。通过这项研究，进一步阐明了 PEG 分子量对 ABC 现象的贡献，为减轻或消除 ABC 现象提供了指导。我们以 2μmol 磷脂 kg 的剂量向比格犬注射不同的 10%PEG 修饰密度的 PEG 修饰乳剂，并在 1 分钟、3 分钟、5 分钟、10 分钟、15 分钟、30 分钟、60 分钟、120 分钟、240 分钟、360 分钟、600 分钟和 24 小时后采集血液样本。然后，使用高效液相色谱法（HPLC）测定药物浓度。结果表明，由于分子量的差异，PEG-DSPE 修饰乳剂的循环时间有显著差异，而 PEG-CHMC 修饰乳剂则没有。低分子量（PEG400、PEG600 和 PEG800）PEG 的空间构象更容易引起强烈的 ABC 现象。我们的工作结果表明循环时间和 PEG 分子量对 ABC 现象的相互作用，表明 PEG 的空间构象具有缓解 ABC 现象的优势。重要的是，这些结果对选择 PEG 化制剂中 PEG 的分子量具有重要意义。
