Hara Eri, Makino Akira, Kurihara Kensuke, Sugai Manabu, Shimizu Akira, Hara Isao, Ozeki Eiichi, Kimura Shunsaku
Department of Experimental Therapeutics, Kyoto University Hospital, Kyoto, Japan.
Biochim Biophys Acta. 2013 Aug;1830(8):4046-52. doi: 10.1016/j.bbagen.2013.03.024. Epub 2013 Mar 29.
Nanoparticle of Lactosome, which is composed of poly(l-lactic acid)-base depsipeptide with diameter of 35nm, 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.
To tumor transplanted mice, Lactosome (0-350mg/kg) was administrated. At 7days after the first administration, indocyanine green (ICG)-labeled Lactosome (ICG-Lactosome, 0-350mg/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).
ICG-Lactosome accumulated in the tumor region when the first Lactosome dose exceeded over 150mg/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 5.0mg/kg, the Lactosome ABC phenomenon can be evaded apparently by dosing ICG-Lactosome over 50mg/kg regardless of anti-Lactosome IgM production.
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.
Lactosome is a potential nanocarrier for drug and/or imaging agent delivery, which can be used for frequent administrations without significant pharmacokinetic alterations.
脂质体纳米粒由聚（L-乳酸）基缩肽组成，直径为35nm，通过增强渗透和滞留（EPR）效应在实体瘤中蓄积。然而，当脂质体重复给药时，观察到其药代动力学发生改变。这种现象被称为脂质体加速血液清除（ABC）现象。在本研究中，研究了脂质体剂量对ABC现象的影响，并从免疫耐受方面进行了讨论。
给肿瘤移植小鼠注射脂质体（0-350mg/kg）。首次给药后7天，注射吲哚菁绿（ICG）标记的脂质体（ICG-脂质体，0-350mg/kg）。进行近红外荧光成像，评估ICG-脂质体的生物分布。此外，通过酶联免疫吸附测定（ELISA）测定抗脂质体IgM的产生量。
当首次脂质体剂量超过150mg/kg时，ICG-脂质体在肿瘤区域蓄积。抗脂质体IgM的量与首次脂质体剂量呈负相关。即使首次脂质体剂量低至5.0mg/kg时建立了脂质体ABC现象，无论抗脂质体IgM的产生情况如何，通过给予超过50mg/kg的ICG-脂质体，脂质体ABC现象也可明显规避。
脂质体ABC现象建立前后存在两种不同的规避机制。然而，在任何一种机制中，通过过量给予脂质体均可规避脂质体ABC现象。
脂质体是一种潜在的药物和/或成像剂递送纳米载体，可用于频繁给药而无明显的药代动力学改变。
