Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes

Abstract

One of the major obstacles to the success of cancer chemotherapy is the multidrug resistance (MDR) often resulting due to the overexpression of drug efflux transporter pumps such as P-glycoprotein (P-gp). Highly efficacious third generation P-gp inhibitors, like tariquidar, have shown promising results in overcoming the MDR. However, P-gp is also expressed in normal tissues like blood brain barrier, gastrointestinal track, liver, spleen and kidney. To maximize the efficacy of P-gp inhibitor and reduce the systemic toxicity, it is important to limit the exposure of P-gp inhibitors and the anticancer drugs to normal tissues and increase their co-localization with tumor cells. In this study, we have investigated the co-delivery of the P-gp inhibitor, tariquidar, and cytotoxic drug, paclitaxel, into tumor cells to reverse the MDR using long-circulating liposomes. Tariquidar- and paclitaxel-loaded long-circulating liposomes showed significant resensitization of the resistant variant for paclitaxel, which could be correlated with an increased accumulation of paclitaxel in tumor cells. These results suggest that the co-delivery of the P-gp inhibitor, tariquidar, and the cytotoxicity inducer, paclitaxel, looks like a promising approach to overcome the MDR.

Figure 1

P-gp expression in SKOV-3 and SKOV-3TR cells as shown by FACS analysis. *P<0.005.

Figure 2

Rh123 uptake study in SKOV-3 and SKOV-3TR cells. The cells were incubated with free tariquidar and tariquidar-loaded liposomes for 30 minutes at the final concentration of 100 nm of tariquidar. After 30 minutes, cells were incubated with 200 ng/ml of Rh123 for 1 hr before analysing for Rh123 uptake using FACS. Cells incubated only with Rh123 were taken as control. Error bars indicate mean ± S.D. *p < 0.05

Figure 3

IC₅₀ for paclitaxel in SKOV-3 and SKOV-3TR cells. Cells were incubated in 96-well plate 24 hrs before the treatment at 3000 cells/well. Cells were than treated with different formulations at various concentrations. Concentrations represents tariquidar and paclitaxel concentration. Error bars indicate mean ± S.D. * p<0.05. X-axis is shown in logarithmic scale. α IC₅₀ for paclitaxel-loaded liposomes in SKOV-3TR cells was not achieved with dose as high as 1000 nM of paclitaxel.