Nuclear localization signal-targeted poly(ethylene glycol) conjugates as potential carriers and nuclear localizing agents for carboplatin analogues
| Autor: | Miguel A. Fuertes, Alberto Gabizon, Dan Gibson, Aviva T. Horowitz, José M. Pérez, Olga Aronov |
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| Rok vydání: | 2004 |
| Předmět: |
Nuclear Localization Signals
Biomedical Engineering Active Transport Cell Nucleus Pharmaceutical Science Bioengineering Antineoplastic Agents Carboplatin Polyethylene Glycols chemistry.chemical_compound DNA Adducts Inhibitory Concentration 50 Mice Drug Delivery Systems Cell Line Tumor medicine NLS Animals Nuclear membrane Pharmacology Cisplatin Microscopy Confocal Molecular Structure Organic Chemistry Cytosol medicine.anatomical_structure chemistry Biochemistry Drug delivery Cancer cell Biophysics Nuclear localization sequence Biotechnology medicine.drug |
| Zdroj: | Bioconjugate chemistry. 15(4) |
| ISSN: | 1043-1802 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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