Targeting the folate receptor (FR): Imaging and cytotoxicity of Re ^I conjugates in FR-overexpressing cancer cells

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]⁺ (γ-4) was screened against an adriamycin- and cisplatin-resistant human ovarian cancer cell line (A2780/AD) that overexpresses the folate receptor (FR). Compound γ-4 was internalized by a folate-receptor-mediated endocytotic pathway, which results in internal accumulation of γ-4. This was contrasted with a FR-negative Chinese hamster ovary cell line in which no internalization of γ-4 was observed. γ-4 was found to be cytotoxic with IC₅₀ values of 189 and 78 μM at 6 and 24 h, respectively, toward the FR-positive cell line. This is in contrast to the IC₅₀ value of 502 μM at 6 h and 84 mu;M at 24 h for cisplatin in the same cell line, with a significantly greater toxicity at the earlier time point. The cytotoxicity of γ-4 as explained by interactions that occur between the rhenium(I) complex moiety and DNA is described.