Liposomal pravastatin inhibits tumor growth by targeting cancer-related inflammation
Liposomal pravastatin inhibits tumor growth by targeting cancer-related inflammation
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DOI：
10.1016/j.jconrel.2010.09.011
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发表时间：
2010-12-20
影响因子：
10.8
通讯作者：
Schiffelers, Raymond M.
中科院分区：
文献类型：
--
作者：
Coimbra, Maria;Banciu, Manuela;Schiffelers, Raymond M.
肿瘤的慢性炎症环境是新的抗肿瘤治疗策略的靶点。除了降低胆固醇的作用外，他汀类药物还具有抗炎和免疫调节的特性。这些多效性效应主要是由于gtp结合蛋白的翻译后修饰发生了改变，gtp结合蛋白调节了许多参与细胞生长和存活的细胞内通路。尽管临床前研究表明他汀类药物可能是有效的抗癌药物，但其剂量要比降低胆固醇水平所需的剂量高100到500倍。此外，鉴于它们对细胞代谢的广泛影响，靶点特异性递送是首选。在这项研究中，我们研究了普伐他汀使用小长循环脂质体的肿瘤特异性递送。体外研究普伐他汀（脂质体）对肿瘤细胞、内皮细胞和巨噬细胞的活力和增殖的影响，发现后者是对（脂质体）普伐他汀治疗最敏感的细胞类型。在体内，与游离普伐他汀相比，脂质体包封的普伐他汀（5 mg/kg）对小鼠b16f10 -黑色素瘤生长的抑制作用超过70%，但普伐他汀无效。正如预期的那样，在研究的时间框架内，治疗并没有影响血清胆固醇水平。注射后48 h，普伐他汀脂质体处理小鼠的肿瘤中仍可检出3 μ g普伐他汀，而游离给药小鼠（即普伐他汀）的肿瘤中未检出普伐他汀。
The chronic inflammatory environment of tumors is a target for novel antitumor therapeutic strategies. Besides cholesterol lowering effects, statins have been studied for their anti-inflammatory and immunomodulatory properties. These pleiotropic effects result mainly from the altered post-translational modification of GTP-binding proteins which regulate many intracellular pathways involved in cell growth and survival. Although pre-clinical studies suggest that statins may be effective anticancer agents required doses that are 100 to 500 fold higher than those needed to lower cholesterol levels. Furthermore, in view of their wide-ranging effects on cellular metabolism, target site-specific delivery is preferred.In this study, we investigated tumor-specific delivery of pravastatin using small long-circulating liposomes. In vitro studies on the effects of (liposomal) pravastatin on viability and proliferation of tumor cells, endothelial cells and macrophages revealed that the latter were the most sensitive cell type towards (liposomal) pravastatin treatment In vivo, liposome-encapsulated pravastatin (5 mg/kg) inhibited murine B16F10-melanoma growth over 70% as compared to free pravastatin, which was ineffective. As expected, treatments did not influence serum cholesterol levels within the time frame of the study. At 48 h post-injection, 3 mu g of pravastatin could still be recovered from the tumors of liposomal pravastatin treated mice, whereas pravastatin could not be detected in tumors of the free drug treated mice (i.e.