College of Pharmacy, Shenyang Pharmaceutical University, No.103 Wenhua Road, Shenyang, 110016, Liaoning, China.
Department of Applied Chemistry, Yuncheng University, Yuncheng, 044000, Shanxi, China.
AAPS PharmSciTech. 2020 Nov 2;21(8):300. doi: 10.1208/s12249-020-01838-2.
PEGylated preparations will be cleared rapidly from blood circulation when they are administrated twice in the same animal at a time interval, referred to as the "accelerated blood clearance" (ABC) phenomenon. Commonly, the study of the ABC phenomenon was investigated in two aspects: induction phase and effectuation phase. Herein, we report the influence of physicochemical properties (PEG molecular weights) in the induction phase and effectuation phase on the ABC phenomenon. In the experiment, on one hand, PEGylated emulsions with different molecular weights of PEG (refer to PEn, n = 400, 600, 800, 1000, 2000, and 5000) were injected for the first dose (induction phase) and induced PE2000 to produce ABC phenomenon. On the other hand, after PE2000 injected, PEn was injected for the second dose (effectuation phase). The results indicated that PE2000 and PE5000 induced an intense ABC phenomenon by their long-circulating characteristic. Interestingly, PE400, PE600, PE800, and PE1000 produced a consistent ABC phenomenon but different circulation time. Apparently, the induction of the ABC phenomenon is not only determined by the circulation time but also by the PEG molecular weights. When PEn is in the effectuation phase, the extent of the ABC phenomenon was not positively related to the molecular weights of PEG, increasing first and then weaken with the increase of molecular weights of PEG. These suggest that the number of -(CHCHO)- repeat units of PE2000 was more conducive to interact with anti-PEG IgM. The results reported here clearly indicate that both the PEG molecular weights of prior dose and the subsequent dose of emulsion strongly influence the extent of the ABC phenomenon. Taken together, our observations in this study complete the effect of PEG molecular weights at a different phase of the ABC phenomenon. Furthermore, our findings have a significant impact on the choice of molecular weights for PEGylated formulations for use in cross-administration.
当同一动物在同一时间间隔内两次给予聚乙二醇化制剂时，它们会从血液循环中迅速清除，这种现象称为“加速血液清除”（ABC）。通常，ABC 现象的研究主要从诱导期和作用期两个方面进行。在此，我们报告了物理化学性质（PEG 分子量）在诱导期和作用期对 ABC 现象的影响。在实验中，一方面，使用不同分子量的 PEG（分别为 PEn，n=400、600、800、1000、2000 和 5000）的聚乙二醇化乳剂进行第一次注射（诱导期），诱导 PE2000 产生 ABC 现象。另一方面，在注射 PE2000 后，注射 PEn 进行第二次注射（作用期）。结果表明，PE2000 和 PE5000 由于其长循环特性而强烈诱导 ABC 现象。有趣的是，PE400、PE600、PE800 和 PE1000 产生了一致的 ABC 现象，但循环时间不同。显然，ABC 现象的诱导不仅取决于循环时间，还取决于 PEG 分子量。当 PEn 处于作用期时，ABC 现象的程度与 PEG 的分子量不成正相关，而是随着 PEG 分子量的增加先增加后减弱。这表明 PE2000 中的-(CHCHO)-重复单元数量更有利于与抗 PEG IgM 相互作用。这里报告的结果清楚地表明，前剂量的 PEG 分子量和随后的乳剂剂量都强烈影响 ABC 现象的程度。总之，我们在这项研究中的观察结果完整地描述了 PEG 分子量在 ABC 现象不同阶段的作用。此外，我们的发现对选择用于交叉给药的聚乙二醇化制剂的分子量具有重要意义。
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