Postdoctoral researcher The Ohio State University Columbus, Ohio, United States
Background: Paclitaxel (Taxol)-induced peripheral neuropathy is a debilitating side effect that is dependent on OATP1B. To further investigate the mechanisms of this toxicity, derivatives of Taxol linked to the drug-like fluorophore Pacific Blue (PB-Taxoids) were synthesized. The purpose of this study was to further evaluate their OATP1B transporter dependency, disposition, antitumor activity, side effects, and explore their utility as fluorescent imaging tools for comparison with paclitaxel both in vitro and in vivo. Methods: Transport studies were performed in HEK293 cells stably transfected with mouse or human OATP1B in the presence or absence of the transport inhibitor nilotinib. Cell viability assays were additionally performed in breast cancer cell lines. The plasma stability of these derivatives was evaluated ex vivo and in vivo, and acute peripheral neuropathy was assessed by the Von Frey Hairs Test in wild type and transporter deficient mice. Results: Transport kinetics show that two related PB-Taxoids have high affinity for OATP1B (Km ~ 100 nM) and their transport can be fully inhibited by nilotinib (Ki ~ 1 µM). Cell viability assays at 72 h demonstrated comparable growth inhibitory properties between these derivatives and paclitaxel. Further ex vivo and in vivo studies showed that these derivatives were stable in plasma and were able to induce peripheral neuropathy to the same extent as paclitaxel. Conclusion: PB-Taxoids have pharmacological features that strongly resemble the parent compound, which provides an opportunity to explore the utility of these compounds as fluorescent imaging tools for future in vitro and in vivo studies to better understand the paclitaxel-related toxicity associated with OATP1B transporters.
