Nuclear localization signal-targeted poly(ethylene glycol) conjugates as potential carriers and nuclear localizing agents for carboplatin analogues
Nuclear localization signal-targeted poly(ethylene glycol) conjugates as potential carriers and nuclear localizing agents for carboplatin analogues
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DOI：
10.1021/bc0499331
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发表时间：
2004-07-01
影响因子：
4.7
通讯作者：
Gibson, D
中科院分区：
文献类型：
--
作者：
Aronov, O;Horowitz, AT;Gibson, D
卡铂是一种低分子抗癌药物，通过与细胞核DNA结合发挥作用。因此，有效地将铂药物输送到癌细胞的细胞核可能会增强药物的细胞毒性。有效地将药物输送到癌细胞的细胞核需要三个层次的定位：靶向肿瘤组织、在癌细胞内积聚和在细胞核内定位。核定位信号(NLS)是一种短小的带正电荷的碱性多肽，它能主动地将大的蛋白质转运到核膜上。我们制备了NLS与聚乙二醇卡铂共轭化合物(NLS-PEGPT)的结合物，并将它们的药理性质与不具有NLS的非靶向类似物(PEGPT)进行了比较。NLS-聚乙二醇铂结合物可迅速内化进入癌细胞，并在细胞核内积聚。尽管它们的核定位很快，但它们形成的铂-DNA加合物比非靶标类似物聚乙二醇铂更少，细胞毒性也更低。这些结果支持卡铂(与顺铂不同)在与核DNA结合之前可能需要胞浆激活的假设。
Carboplatin is a low-molecular-weight anticancer drug that acts by binding to the nuclear DNA of cells. Thus, efficient delivery of the platinum drugs to the nucleus of the cancer cells may enhance the cytotoxicity of the drug. Efficient drug delivery to the nucleus of cancer cells requires three levels of localization: targeting to the cancerous tissue, accumulation in the cancer cells, and intracellular localization in the nucleus. Nuclear localization signals (NLS) are short positively charged basic peptides that actively transport large proteins across the nuclear membrane. We have prepared conjugates in which the NLS is tethered to poly(ethyleneglycol)carboplatin conjugate (NLS-PEG-Pt) and compared their pharmacological properties to those of their untargeted analogues that do not possess the NLS (PEG-Pt). NLS-PEG-Pt conjugates are rapidly internalized into cancer cells and accumulate in the nucleus. Despite their rapid nuclear localization, they form less Pt-DNA adducts than the untargeted analogues, PEG-Pt, and are also less cytotoxic. These results support the hypothesis that carboplatin (unlike cisplatin) may require cytosolic activation prior to its binding to nuclear DNA.