title: Targeting the folate receptor (FR): imaging and cytotoxicity of ReI conjugates in FR-overexpressing cancer cells.
abstract: The synthesis, characterization, in vitro imaging, and cytotoxic properties of a new folate conjugate of rhenium(I) are reported. The conjugate [FA-PEG-BQAV-Re(CO)3]+ (gamma-4) was screened against an adriamycin- and cisplatin-resistant human ovarian cancer cell line (A2780/AD) that overexpresses the folate receptor (FR). Compound gamma-4 was internalized by a folate-receptor-mediated endocytotic pathway, which results in internal accumulation of gamma-4. This was contrasted with a FR-negative Chinese hamster ovary cell line in which no internalization of gamma-4 was observed. gamma-4 was found to be cytotoxic with IC(50) values of 189 and 78 microM at 6 and 24 h, respectively, toward the FR-positive cell line. This is in contrast to the IC(50) value of 502 microM at 6 h and 84 microM at 24 h for cisplatin in the same cell line, with a significantly greater toxicity at the earlier time point. The cytotoxicity of gamma-4 as explained by interactions that occur between the rhenium(I) complex moiety and DNA is described.
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, NY 13244-4100, USA.
authors.forename: Nerissa
authors.initials: N
authors.lastname: Viola-Villegas
authors.forename: Amy E
authors.initials: AE
authors.lastname: Rabideau
authors.forename: Justin
authors.initials: J
authors.lastname: Cesnavicious
authors.forename: Jon
authors.initials: J
authors.lastname: Zubieta
authors.forename: Robert P
authors.initials: RP
authors.lastname: Doyle
mesh_terms: D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000737:chemistry / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018613:Microscopy, Confocal; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012211:Rhenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
chemical_list: D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D007364:Intercalating Agents; D009942:Organometallic Compounds; D011956:Receptors, Cell Surface; D059004:Topoisomerase I Inhibitors; D012211:Rhenium; D004247:DNA; D005492:Folic Acid; D004264:DNA Topoisomerases, Type I