title: Folate-targeted PEG as a potential carrier for carboplatin analogs. Synthesis and in vitro studies.
abstract: Like most low molecular weight drugs, carboplatin has a short blood circulation time, which reduces tumor uptake and intracellular DNA binding. Drugs conjugated to PEG carriers benefit from prolonged blood circulation, but suffer from reduced cell permeability. In this work we attempted to develop long-circulating PEGylated carboplatin analogues with improved cell permeation abilities, by conjugating the platinum moiety to folate-targeted PEG carriers capable of utilizing the folate receptor-mediated endocytosis (FRME). Two bifunctional FA-PEG conjugates, FA-PEG-Pt and FA-PEG-FITC, were prepared, and their cell uptake, DNA binding, and cytotoxicity were studied by fluorescent microscopy, FACS, and platinum analysis. Folate-targeted PEG conjugates enter the cells efficiently by the FRME pathway but form relatively few DNA adducts and have higher IC(50) values than carboplatin and their nontargeted analogues. Nontargeted PEG-Pt conjugates have a lower cellular uptake but produce higher levels of DNA binding and improved cytotoxicity. Carboplatin, used as a control, has the fastest cellular uptake, but after 16 h of postincubation a large percentage of the drug is excreted from the cells. The findings of this study suggest that folate-targeted conjugates such as FA-PEG-Pt, may not be an optimal prodrug for the carboplatin family compounds, because the conjugates or the active moieties are neutralized or blocked during the FRME process and do not manage to effectively reach the nuclear DNA.
authors.affiliation: Department of Medicinal Chemistry and Natural Products, School of Pharmacy, P. O. Box 12065, The Hebrew University of Jerusalem, 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: Dan
authors.initials: D
authors.lastname: Gibson
mesh_terms: D000818:Animals; D016190:Carboplatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D058973:Folate Receptors, GPI-Anchored; D051379:Mice; D008807:Mice, Inbred BALB C; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D011956:Receptors, Cell Surface
chemical_list: D002352:Carrier Proteins; D004337:Drug Carriers; D058973:Folate Receptors, GPI-Anchored; D011956:Receptors, Cell Surface; D011092:Polyethylene Glycols; D016190:Carboplatin