Evasion from accelerated blood clearance of nanocarrier named as "Lactosome" induced by excessive administration of Lactosome
Evasion from accelerated blood clearance of nanocarrier named as "Lactosome" induced by excessive administration of Lactosome
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DOI：
10.1016/j.bbagen.2013.03.024
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发表时间：
2013-08-01
影响因子：
3
通讯作者：
Kimura, Shunsaku
中科院分区：
文献类型：
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作者：
Hara, Eri;Makino, Akira;Kimura, Shunsaku
背景：乳糖体纳米颗粒由直径为35 nm的聚(L-乳酸)基缩肽组成，通过增强通透性和滞留(EPR)效应在实体瘤中积累。然而，当重复施用乳糖体时，观察到乳糖体的药代动力学改变。这种现象被称为乳糖体加速血液清除（ABC）现象。本研究从免疫耐受的角度探讨了Lactosome剂量对ABC现象的影响并进行了讨论。方法：对肿瘤移植小鼠给予Lactosome（0-350mg/kg）。首次给药后7天，注射吲哚菁绿（ICG）标记的乳糖体（ICG-Lactosome，0-350 mg/kg）。进行近红外荧光成像，并评估 ICG-Lactosome 的生物分布。此外，通过酶联免疫吸附测定(ELISA)测定抗乳糖体IgM的产生量。结果：当首次乳糖体剂量超过150mg/kg时，ICG-乳糖体在肿瘤区域积聚。抗乳糖体 IgM 的量与首次乳糖体剂量呈负相关。即使在首次乳糖体剂量低至 5.0 mg/kg 的乳糖体 ABC 现象建立后，无论抗乳糖体 IgM 的产生如何，通过给予 ICG-Lactosome 超过 50 mg/kg 都可以明显避免乳糖体 ABC 现象。结论：在乳糖体 ABC 现象建立之前和之后，有两种不同的逃避机制。然而，无论哪种机制，乳糖体ABC现象都可以通过过量施用乳糖体来避免。一般意义：乳糖体是药物和/或显像剂递送的潜在纳米载体，可用于频繁施用而不会显着药代动力学改变。 (c) 2013 Elsevier B.V. 保留所有权利。
Background: Nanoparticle of Lactosome, which is composed of poly(L-lactic acid)-base depsipeptide with diameter of 35 nm, accumulates in solid tumors by the enhanced permeability and retention (EPR) effect. However, a pharmacokinetic alteration of Lactosome was observed when Lactosome was repeatedly administered. This phenomenon is named as the Lactosome accelerated blood clearance (ABC) phenomenon. In this study, the effect of Lactosome dose on the ABC phenomenon was examined and discussed in terms of immune tolerance.Methods: To tumor transplanted mice, Lactosome (0-350 mg/kg) was administrated. At 7 days after the first administration, indocyanine green (ICG)-labeled Lactosome (ICG-Lactosome, 0-350 mg/kg) was injected. Near-infrared fluorescence imaging was performed, and biodistribution of ICG-Lactosome was evaluated. Further, the produced amounts of anti-Lactosome IgM were determined by enzyme-linked immunosorbent assay (ELISA).Results: ICG-Lactosome accumulated in the tumor region when the first Lactosome dose exceeded over 150 mg/kg. The amounts of anti-Lactosome IgM were inversely correlated with the first Lactosome doses. Even after establishment of the Lactosome ABC phenomenon with the first Lactosome dose as low as 5.0 mg/kg, the Lactosome ABC phenomenon can be evaded apparently by dosing ICG-Lactosome over 50 mg/kg regardless of anti-Lactosome IgM production.Conclusions: There are two different mechanisms for evasion from the Lactosome ABC phenomenon before and after its establishment. In either mechanism, however, the Lactosome ABC phenomenon can be evaded by excessive administration of Lactosome.General significance: Lactosome is a potential nanocarrier for drug and/or imaging agent delivery, which can be used for frequent administrations without significant pharmacokinetic alterations. (c) 2013 Elsevier B.V. All rights reserved.