Inducing cell death in vitro in cancer cells by targeted delivery of cytochrome c via a transferrin conjugate.
Inducing cell death in vitro in cancer cells by targeted delivery of cytochrome c via a transferrin conjugate.
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DOI：
10.1371/journal.pone.0195542
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Griebenow K
中科院分区：
文献类型：
--
作者：
Saxena M;Delgado Y;Sharma RK;Sharma S;Guzmán SLPL;Tinoco AD;Griebenow K
目前使用的许多抗癌药物的主要缺点之一是脱靶效应。有针对性的递送是最大程度地减少此类不良事件的一种方法。为了主动靶向肺癌细胞，我们开发了凋亡诱导蛋白细胞色素 c 与转铁蛋白的缀合物，因为转铁蛋白受体在许多快速分裂的癌细胞中过度表达。细胞色素 c 和转铁蛋白通过氧化还原敏感的二硫键交联，以便在转铁蛋白受体的内吞作用下在细胞内释放蛋白质。共聚焦结果证明转铁蛋白受体过表达 A549 肺癌细胞对细胞色素 c-转铁蛋白缀合物的细胞摄取。定位研究进一步证实该缀合物逃离了内体。此外，体外测定表明该缀合物可以通过激活 caspase-3 诱导细胞凋亡。新缀合物不仅在 A549 癌细胞中保持与众所周知的药物顺铂 (50 μM) 相似的 IC50 值，而且对正常肺 (MRC5) 细胞无毒。我们的新结合物有望在未来开发出增强转铁蛋白受体表达的靶向癌症。
One of the major drawbacks of many of the currently used cancer drugs are off-target effects. Targeted delivery is one method to minimize such unwanted and detrimental events. To actively target lung cancer cells, we have developed a conjugate of the apoptosis inducing protein cytochrome c with transferrin because the transferrin receptor is overexpressed by many rapidly dividing cancer cells. Cytochrome c and transferrin were cross-linked with a redox sensitive disulfide bond for the intra-cellular release of the protein upon endocytosis by the transferrin receptor. Confocal results demonstrated the cellular uptake of the cytochrome c-transferrin conjugate by transferrin receptor overexpressing A549 lung cancer cells. Localization studies further validated that this conjugate escaped the endosome. Additionally, an in vitro assay showed that the conjugate could induce apoptosis by activating caspase-3. The neo-conjugate not only maintained an IC50 value similar to the well known drug cisplatin (50 μM) in A549 cancer cells but also was nontoxic to the normal lung (MRC5) cells. Our neo-conjugate holds promise for future development to target cancers with enhanced transferrin receptor expression.
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影响因子：
5.3
作者：
Deming, PB;Schafer, ZT;Kornbluth, S
通讯作者：
Kornbluth, S
影响因子：
4.7
作者：
Derfus, Austin M.;Chen, Alice A.;Bhatia, Sangeeta N.
通讯作者：
Bhatia, Sangeeta N.
谷胱甘肽响应纳米载体作为靶向细胞内药物和基因递送的有前途的平台
影响因子：
10.8
作者：
Cheng, Ru;Feng, Fang;Zhong, Zhiyuan
通讯作者：
Zhong, Zhiyuan
影响因子：
4.8
作者：
Drin, G;Cottin, S;Temsamani, J
通讯作者：
Temsamani, J
DOI：
10.1073/pnas.89.7.3070
发表时间：
1992-04-01
影响因子：
11.1
作者：
GODWIN, AK;MEISTER, A;ANDERSON, ME
通讯作者：
ANDERSON, ME