Polymeric micelles containing reversibly phospholipid-modified anti-survivin siRNA: a promising strategy to overcome drug resistance in cancer.
Polymeric micelles containing reversibly phospholipid-modified anti-survivin siRNA: a promising strategy to overcome drug resistance in cancer.
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DOI：
10.1016/j.canlet.2013.09.037
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发表时间：
2014-02-28
期刊：
影响因子：
9.7
通讯作者：
Torchilin, V. P.
中科院分区：
文献类型：
--
作者：
Salzano, G.;Riehle, R.;Navarro, G.;Perche, F.;De Rosa, G.;Torchilin, V. P.
生存素是一种抗凋亡的小分子蛋白，它与化疗耐药性有关，这一发现为克服癌症耐药性开辟了新的前景。结果表明，siRNA能有效抑制肿瘤细胞中survivin的表达。然而，siRNA的临床应用仍然受到不利的药代动力学特征的阻碍。为了解决这个问题，我们开发了一种新的系统来将siRNA递送到癌细胞中。也就是说，我们通过可还原的二硫键用硫代磷酸乙醇（PE）部分可逆地修饰了生存素siRNA，并将所得的siRNA-S-S-PE缀合物掺入基于纳米聚乙二醇2000-磷脂酰乙醇胺（PEG 2000-PE）的聚合物胶束（PM）中，获得生存素siRNA PM。通过存活素蛋白下调、肿瘤细胞生长抑制和经处理的肿瘤细胞对紫杉醇（PXL）的化学增敏来评价这些纳米制剂的活性。我们发现在几种癌细胞系中，用Survivin siRNA PM处理后，细胞活力显著降低，Survivin蛋白水平下调。此外，通过用生存素siRNA PM处理细胞而下调生存素，在敏感和抗性癌细胞系中引起细胞对PXL的显著敏化。最后，我们证明了在同一PM中成功地共同递送PXL和生存素siRNA，导致与它们的顺序施用相比具有上级治疗活性。我们的研究结果支持使用这种新平台治疗最具侵袭性的肿瘤。
The discovery that survivin, a small anti-apoptotic protein, is involved in chemoresistance, opens a new scenario to overcome the drug resistance in cancer. It was shown that siRNA can efficiently inhibit the expression of survivin in cancer cells. However, the clinical use of siRNA is still hampered by an unfavorable pharmacokinetic profile. To address this problem, earlier we developed a novel system to deliver siRNA into cancer cells. Namely, we reversibly modified the survivin siRNA with a phosphothioethanol (PE) portion via a reducible disulfide bond and incorporated the resulting siRNA-S-S-PE conjugate into nanosized polyethyelene glycol2000-phosphatidyl ethanolamine (PEG2000-PE)-based polymeric micelles (PM), obtaining survivin siRNA PM. The activity of these nanopreparations was evaluated by survivin protein down-regulation, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to paclitaxel (PXL). We found a significant decrease of cell viability and down-regulation of survivin protein levels after treatment with survivin siRNA PM in several cancer cell lines. In addition, the down-regulation of survivin by treating cells with survivin siRNA PM, elicited a significant sensitization of the cells to PXL, in both sensitive and resistant cancer cell lines. Finally, we demonstrate successful co-delivery of PXL and survivin siRNA in the same PM leading to superior therapeutic activity compared to their sequential administration. Our results support the use of this new platform for the treatment of the most aggressive tumors.
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影响因子：
12.4
作者：
Seth, Shaguna;Matsui, Yoshiyuki;Polisky, Barry
通讯作者：
Polisky, Barry
影响因子：
3.5
作者：
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影响因子：
82.9
作者：
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Altieri, DC
DOI：
10.1038/nrd2742
发表时间：
2009-03
期刊：
Nature reviews. Drug discovery
影响因子：
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作者：
Whitehead KA;Langer R;Anderson DG
通讯作者：
Anderson DG
DOI：
10.1016/j.ijrobp.2006.06.049
发表时间：
2006-11-01
影响因子：
7
作者：
Sah, Nand K.;Munshi, Anupama;Meyn, Raymond E.
通讯作者：
Meyn, Raymond E.