A frustrating problem: accelerated blood clearance of PEGylated solid lipid nanoparticles following subcutaneous injection in rats.
A frustrating problem: accelerated blood clearance of PEGylated solid lipid nanoparticles following subcutaneous injection in rats.
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DOI：
10.1016/j.ejpb.2012.04.023
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发表时间：
2012-08
期刊：
影响因子：
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通讯作者：
Y. Zhao;Chunling Wang;Long Wang;Qiang Yang;Wenya Tang;Zhennan She;Yihui Deng
中科院分区：
文献类型：
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作者：
Y. Zhao;Chunling Wang;Long Wang;Qiang Yang;Wenya Tang;Zhennan She;Yihui Deng
皮下给药后，胶体颗粒优先进入淋巴系统，通过药物在局部淋巴结中的蓄积实现淋巴靶向。此外，表面聚乙二醇化的胶体颗粒显示出增强的引流到淋巴管中，并在皮下注射后被局部淋巴结的巨噬细胞摄取。然而，据报道，在重复静脉内注射时，通过施用PEG化胶体颗粒产生的PEG特异性IgM显著加速后续剂量的PEG化颗粒的清除。在这篇文章中，我们报告了第一次皮下注射聚乙二醇化固体脂质纳米粒也诱导静脉内给药的聚乙二醇化颗粒从循环中非常迅速地清除，并且皮下注射的“ABC指数”（加速血液清除强度的参数）等于或甚至低于第一次静脉内注射后的指数。此外，第一次s.c.剂量，但第二次静脉注射剂量的消除率显著更高，强烈表明，除了脾脏外，局部淋巴结也在这种现象中起促进作用，尽管引起这种现象的确切淋巴细胞仍不清楚。因此，我们的观察结果可能对考虑使用需要不同给药途径（如静脉内和皮下注射）的聚乙二醇化产物的联合治疗具有重要意义，并且需要非常小心。
Colloidal particles have preferential access to the lymphatic system following subcutaneous administration, achieving lymphatic targeting by drug accumulation in the regional lymph nodes. Moreover, the surface PEGylated colloidal particles have shown enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes after subcutaneous injection. Nevertheless, it is reported that upon repeated intravenous injection, the PEG-specific IgM produced by the administration of the PEGylated colloidal particles markedly accelerates the clearance of subsequent doses of PEGylated particles. In this article, we report that the first subcutaneous injection of PEGylated solid lipid nanoparticles also induces the intravenously administered PEGylated particles to be cleared very rapidly from the circulation, and the “ABC index,” a parameter for the intensity of accelerated blood clearance, for subcutaneous injection was equivalent to or even lower than that following the first intravenous injection. Moreover, the small quantities of distributed particles in the spleen after the first s.c. dose but the significantly higher elimination rate of the second i.v. dose, strongly suggest that, in addition to the spleen, the regional lymph nodes also play a promotive role in this phenomenon, although the exact lymphocytes causing this phenomenon remain unclear. Our observations may thus have important implications for considering combination therapy with PEGylated productions requiring different administration routes such as intravenous and subcutaneous injection, and great care is needed.