Cyclodextrin-mediated entrapment of curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA in liposomes for treatment of xenograft lung tumor in rats.
Cyclodextrin-mediated entrapment of curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA in liposomes for treatment of xenograft lung tumor in rats.
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DOI：
10.1016/j.colsurfb.2011.01.023
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发表时间：
2011-06-01
影响因子：
5.8
通讯作者：
Awasthi, Vibhudutta
中科院分区：
文献类型：
--
作者：
Agashe, Hrushikesh;Sahoo, Kaustuv;Lagisetty, Pallavi;Awasthi, Vibhudutta
我们最近报道了一种新的姜黄素4-[3，5-双（2-氯亚苄基-4-氧代-哌啶-1-基）-4-氧代-2-丁烯酸]或CLEFMA作为一种有效的抗增殖剂，并表明它诱导肺癌细胞的自噬细胞死亡。我们现在报道了一种药物-CD-脂质体方法来配制CLEFMA脂质体，该脂质体可以用Tc-99 m放射性核素标记，用于其生物分布的非侵入性成像。通过羟丙基-β-环糊精实现CLEFMA包封。体外研究表明，CLEFMA对肺腺癌H441细胞具有比天然姜黄素更强的抗增殖活性。同时对正常肺成纤维细胞的增殖能力无影响。CLEFMA脂质体保留了游离CLEFMA的抗增殖效力，同时保持其在正常肺成纤维细胞中的无毒性质。在携带异种移植H441肿瘤的裸鼠中，用CLEFMA脂质体静脉内治疗后肿瘤体积显著减小（p<0.05）;肿瘤抑制被确定为94%。CLEFMA脂质体的抗肿瘤活性通过观察到治疗大鼠的肿瘤中的F-18-氟脱氧葡萄糖摄取与对照大鼠的那些相比减少而证实。Tc-99 m标记的CLEFMA脂质体在肝脏中蓄积（33.7%）;脾脏显示每克组织基础上的最大蓄积（6.2%/g）。在肝、肺和肾的组织病理学检查后，我们发现多次给予CLEFMA脂质体没有明显的毒性。结果证明了脂质体用作CLEFMA载体的效用。这项研究是第一个证明新型姜黄素CLEFMA在临床前模型中的疗效。
We recently reported a novel curcuminoid 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] or CLEFMA as a potent anti-proliferative agent, and showed that it induces autophagic cell death in lung cancer cells. We are now reporting a drug-in-CD-in-liposome approach to formulate CLEFMA liposomes that could be labeled with Tc-99m radionuclide for non-invasive imaging of their biodistribution. CLEFMA encapsulation was enabled by hydroxypropyl-β-cyclodextrin. In vitro studies showed that CLEFMA possessed more potent anti-proliferative activity in lung adenocarcinoma H441 cells than naturally occurring curcumin. At the same time, it had no effect on the proliferative capacity of normal lung fibroblasts. CLEFMA liposomes retained the antiproliferative potency of free CLEFMA, while maintaining its non-toxic nature in normal lung fibroblasts. In nude rats bearing xenograft H441 tumors, the tumor volume significantly reduced after i.v. treatment with CLEFMA liposomes (p<0.05); the tumor inhibition was determined to be 94%. The anti-tumor activity of CLEFMA liposomes was confirmed by the observation that F-18-fluorodeoxyglucose uptake in tumors of treated rats was reduced as compared to those of control rats. Tc-99m-labeled CLEFMA liposomes accumulated in liver (33.7%); spleen showed the largest accumulation on per gram tissue basis (6.2 %/g). Upon histopathological examination of liver, lung and kidney, we found no apparent toxicity from multiple CLEFMA liposome administrations. The results demonstrate the utility of liposomes to serve as a carrier for CLEFMA. This study is the first to demonstrate the efficacy of novel curcuminoid CLEFMA in a preclinical model.
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