title: Nuclear localization signal-targeted poly(ethylene glycol) conjugates as potential carriers and nuclear localizing agents for carboplatin analogues.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Natural Products, School of Pharmacy, P.O. Box 12065, The Hebrew University of Jerusalem, 91120, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Aronov
authors.forename: Aviva T
authors.initials: AT
authors.lastname: Horowitz
authors.forename: Alberto
authors.initials: A
authors.lastname: Gabizon
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Fuertes
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Pérez
authors.forename: Dan
authors.initials: D
authors.lastname: Gibson
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D016190:Carboplatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D020128:Inhibitory Concentration 50; D051379:Mice; D018613:Microscopy, Confocal; D015394:Molecular Structure; D019913:Nuclear Localization Signals / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D019913:Nuclear Localization Signals; D011092:Polyethylene Glycols; D016190:Carboplatin