Pt-rotaxanes as cytotoxic agents

Cytotoxic agents that specifically target cancer cells are in high demand. Modifying drugs with targeting groups however, can produce deleterious effects on drug pharmokinetics. In this study, platinum (Pt) was linked with host-rotaxanes to discover the effect on the cytotoxicity of Pt when carried by a highly modified rotaxane as a ligand. One host-rotaxane (Pt-BocRot) contains the basic components of a rotaxane: wheel (with a Boc protecting group), axle, and blocking group. A second rotaxane (Pt-ArgRot) contains arginine moieties on its wheel instead to potentially improve association with the phosphate groups on cell membranes or DNA backbone. The cytotoxicities of the rotaxanes and various model compounds were determined using ovarian cancer SKOV-3 cell line, which is resistant to cisplatin. We found Pt-ArgRot was slightly more cytotoxic than Pt-BocRot. Both were clearly more cytotoxic than rotaxanes without Pt and the model compounds. As importantly, they killed cells through an apoptotic mechanism. These results suggest that targeting agents for a particular cell type can be incorporated with Pt-complexes using the rotaxane architecture to improve drug specificity.