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.

• Authors: Niravkumar R Patel, Alok Rathi, Dmitriy Mongayt, Vladimir P Torchilin
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 416 Issue 1 Pg. 296-9 (Sep 15 2011) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 21703341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Liposomes
• Quinolines
• Rhodamine 123
• tariquidar
• Paclitaxel

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, biosynthesis)
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor (methods)
• Humans
• Liposomes (administration & dosage, chemical synthesis)
• Molecular Targeted Therapy (methods)
• Paclitaxel (administration & dosage, pharmacology)
• Particle Size
• Quinolines (administration & dosage, pharmacology)
• Rhodamine 123 (metabolism)
• Surface Properties