Regression of Atherosclerotic Plaques of Cholesterol-Fed Rabbits by Combined Chemotherapy With Paclitaxel and Methotrexate Carried in Lipid Core Nanoparticles
Regression of Atherosclerotic Plaques of Cholesterol-Fed Rabbits by Combined Chemotherapy With Paclitaxel and Methotrexate Carried in Lipid Core Nanoparticles
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DOI：
10.1177/1074248418778836
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发表时间：
2018-11-01
影响因子：
2.6
通讯作者：
Serrano, Carlos V., Jr.
中科院分区：
文献类型：
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作者：
Gomes, Fernando L. T.;Maranhao, Raul C.;Serrano, Carlos V., Jr.
在先前的研究中，已经证明脂质核心纳米颗粒（LDE）类似于低密度脂蛋白结构，并且携带抗增殖剂紫杉醇（PTX），强烈地减少由胆固醇喂养诱导的兔中的动脉粥样硬化病变。目前，目的是验证LDE-PTX治疗与甲氨蝶呤（MTX）联合LDE（LDE-MTX）是否可以加速在停止胆固醇喂养后用单一LDE-PTX治疗获得的动脉粥样硬化消退。38只家兔饲喂1%胆固醇饲料8周。然后对这些家兔中的6只实施安乐死，以分析主动脉（对照）。在其余家兔中，停止胆固醇喂养，并将这32只动物分配至3组，接受不同的8周静脉给药，每周一次：LDE-PTX（n = 10; 4 mg/kg）、LDE-PTX + LDE-MTX（n = 11; 4 mg/kg）和LDE单药（n = 11）。然后对家兔实施安乐死，并切除椎间盘进行形态测定、免疫组织化学和基因表达分析。在胆固醇喂养停药后，与单独的LDE组相比，LDE-PTX和LDE-PTX + LDE-MTX治疗均具有增加斑块面积消退的能力：LDE-PTX为-49%，LDE-PTX + LDE-MTX为-59%。然而，仅LDE-PTX + LDE-MTX治疗引起内膜面积减少，估计为-57%。LDE-PTX和LDE-PTX + LDE-MTX治疗使主动脉病变中的巨噬细胞减少48%和43%。基质金属蛋白酶9被LDE-PTX（74%）或LDE-PTX + LDE-MTX（78%）降低。LDE-PTX和LDE-PTX + LDE-MTX分别使肿瘤坏死因子基因表达降低65%和79%。总之，LDE-PTX治疗确实加速了胆固醇喂养后的斑块减少; LDE-PTX + LDE-MTX进一步增加了这种作用，没有观察到任何毒性。这些结果为使用联合化疗对严重的、高度炎症的动脉粥样硬化病变产生更强的作用铺平了道路。
In previous studies, it was demonstrated that lipid core nanoparticles (LDE) resemble the low-density lipoprotein structure and carrying the antiproliferative agent paclitaxel (PTX) strongly reduced atherosclerosis lesions induced in rabbits by cholesterol feeding. Currently, the aim was to verify whether combining LDE-PTX treatment with methotrexate (MTX) associated with LDE (LDE-MTX) could accelerate the atherosclerosis regression attained with single LDE-PTX treatment, after withdrawing the cholesterol feeding. Thirty-eight rabbits were fed 1% cholesterol chow for 8 weeks. Six of these rabbits were then euthanized for analyses of the aorta (controls). In the remaining rabbits, cholesterol feeding was withdrawn, and those 32 animals were allocated to 3 groups submitted to different 8-week intravenous treatments, all once/week: LDE-PTX (n = 10; 4 mg/kg), LDE-PTX + LDE-MTX (n = 11; 4 mg/kg), and LDE-alone (n = 11). Rabbits were then euthanized and aortas were excised for morphometric, immunohistochemical, and gene expression analyses. After cholesterol feeding withdrawal, in comparison with LDE-alone group, both LDE-PTX and LDE-PTX + LDE-MTX treatments had the ability to increase the regression of plaque areas: -49% in LDE-PTX and -59% for LDE-PTX + LDE-MTX. However, only LDE-PTX + LDE-MTX treatment elicited reduction in the intima area, estimated in -57%. Macrophage presence in aortic lesions was reduced 48% by LDE-PTX and 43% by LDE-PTX + LDE-MTX treatment. Matrix metalloproteinase 9 was reduced by either LDE-PTX (74%) or LDE-PTX + LDE-MTX (78%). Tumor necrosis factor gene expression was reduced 65% by LDE-PTX and 79% by LDE-PTX + LDE-MTX. In conclusion, treatment with LDE-PTX indeed accelerated plaque reduction after cholesterol feeding; LDE-PTX + LDE-MTX further increased this effect, without any observed toxicity. These results pave the way for the use of combined chemotherapy to achieve stronger effects on aggravated, highly inflamed atherosclerotic lesions.