Nuclear Localization Signal-Targeted Poly(ethylene glycol) Conjugates as Potential Carriers and Nuclear Localizing Agents for Carboplatin Analogues

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• 作者：Olga Aronov ; Aviva T. Horowitz ; Alberto Gabizon ; Miguel A. Fuertes ; José ; Manuel Pé ; rez ; and Dan Gibson
• 刊名：Bioconjugate Chemistry
• 出版年：2004
• 出版时间：July 2004
• 年：2004
• 卷：15
• 期：4
• 页码：814 - 823
• 全文大小：276K
• 年卷期：v.15,no.4(July 2004)
• ISSN：1520-4812

文摘

Carboplatin is a low-molecular-weight anticancer drug that acts by binding to the nuclear DNA ofcells. Thus, efficient delivery of the platinum drugs to the nucleus of the cancer cells may enhancethe cytotoxicity of the drug. Efficient drug delivery to the nucleus of cancer cells requires three levelsof localization: targeting to the cancerous tissue, accumulation in the cancer cells, and intracellularlocalization in the nucleus. Nuclear localization signals (NLS) are short positively charged basicpeptides that actively transport large proteins across the nuclear membrane. We have preparedconjugates 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 notpossess the NLS (PEG-Pt). NLS-PEG-Pt conjugates are rapidly internalized into cancer cells andaccumulate in the nucleus. Despite their rapid nuclear localization, they form less Pt-DNA adductsthan the untargeted analogues, PEG-Pt, and are also less cytotoxic. These results support thehypothesis that carboplatin (unlike cisplatin) may require cytosolic activation prior to its binding tonuclear DNA.