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.

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

“…Earlier studies have shown that these nano-sized particles, like lipids, micelles, and inorganic hybrid particles, can bypass the P-gp efflux pumps and modify the intracellular accumulation of chemotherapeutic drugs Patel et al, 2011;Li et al, 2012). Multidrug resistance may be treated using a mixture of entrapped cytotoxic drugs and chemo sensitizers.…”

The comparison of protein-entrapped liposomes and lipoparticles: preparation, characterization, and efficacy of cellular uptake

“…[1][2][3][4] In particular, liposomes are well recognized as pharmaceutical carriers because of their biocompatibility, biodegradability, and low toxicity and are clinically used for efficacy enhancement and toxicity reduction. 5,6 Liposomes have good longevity in the blood that allows their accumulation in pathological areas with compromised vasculature, can demonstrate specific targeting to disease sites when various targeting ligands are attached to their surface to enhance intracellular penetration, possess stimulus-sensitivity allowing for drug release from the carriers under certain pathological conditions, and show contrast properties with loading of various contrast materials that allows for direct visualization in vivo.…”

Co-delivery nanoparticles of anti-cancer drugs for improving chemotherapy efficacy

“…Patel et al had investigated the co-delivery of ariquidar and PTX into tumor cells to reverse the MDR using long-circulating liposomes. Tariquidar-and PTX-loaded long-circulating liposomes showed significant re-sensitization of the resistant variant for paclitaxel, which could be correlated with an increased accumulation of PTX in tumor cells (Patel et al, 2011). Can et al had developed PEG-PE-based long-circulating micelles co-loaded with elacridar and PTX, and investigated their ability to overcome PTX resistance in two cancer cell lines.…”