Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: Internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death
Physicochemical parameters affecting liposomal bisphosphonates bioactivity for restenosis therapy: Internalization, cell inhibition, activation of cytokines and complement, and mechanism of cell death
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DOI：
10.1016/j.jconrel.2010.03.011
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发表时间：
2010-09-01
影响因子：
10.8
通讯作者：
Golomb, Gershon
中科院分区：
文献类型：
--
作者：
Epstein-Barash, Hila;Gutman, Dikla;Golomb, Gershon
双膦酸脂质体（LIP-Bps）对单核/巨噬细胞的部分失活和短暂消耗在包括再狭窄在内的各种炎症疾病中得到了广泛的实验。以往关于LIP-Bps活化细胞因子的研究仅限于某些细胞系。此外，体外和体内研究与补体(C)激活之间的相关性尚未报道。本文报道了LIP-Bps对多种细胞内化和增殖、细胞死亡机制、细胞因子（体外和体内）和C活化（大鼠、兔和猪）的生物活性的全面研究。以下参数的作用已经确定：1)药物类型（氯膦酸钠/阿仑膦酸钠）；Ii)囊泡大小（60-800 nm）；Iii)电荷（中性/负电荷/正电荷）；细胞培养类型（各种细胞系和原代培养）。我们发现单核/巨噬细胞抑制和细胞因子激活依赖于细胞类型，与大鼠和家兔再狭窄模型中获得的生物活性相关性有限。带负电荷的脂质体（85 +/- 20 nm）有效地消耗了兔的单核细胞（消耗67%），细胞因子的少量激活和C的无激活。因此，细胞培养不足以评估细胞因子的活性，通过控制LIP-BP的性质（大小、电荷和药物类型）可以获得最佳的生物活性。(C) 2010 Elsevier B.V.版权所有
Partial inactivation and transient depletion of monocytes/macrophages by liposomal bisphosphonates (LIP-Bps) is widely experimented in various inflammatory disorders including restenosis. Previous studies on activation of cytokines by LIP-Bps are limited to certain cell lines. Moreover, the correlation between in vitro and in vivo studies and complement (C) activation has not been reported. We report here a comprehensive study on the bioactivity of LIP-Bps on various cells' internalization and proliferation, mechanism of cell death, cytokines (in vitro and in vivo) and C activation (in the rat, rabbit and pig). The role of the following parameters has been determined i) drug type (clodronate/alendronate); ii) vesicles size (60-800 nm); iii) charge (neutral/negative/positive); and iv) cell culture type (various cell lines and primary cultures). It was found that monocyte/macrophage inhibition and cytokine activation depend on the cell type, with a limited correlation to the bioactivity obtained in the rat and rabbit models of restenosis. Negatively charged liposomes (85 +/- 20 nm) effectively depleted rabbit's monocytes (67% depletion), with a minor activation of cytokines and no C activation. It is concluded that cell culture studies are insufficient for assessing cytokine activation, and that by controlling LIP-BP properties (size, charge and drug type) optimal bioactivity could be achieved. (C) 2010 Elsevier B.V. All rights reserved.