title: 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.affiliation: Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA.
authors.forename: Niravkumar R
authors.initials: NR
authors.lastname: Patel
authors.forename: Alok
authors.initials: A
authors.lastname: Rathi
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Mongayt
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000138:chemical synthesis*; D058990:Molecular Targeted Therapy / Q000379:methods*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D010316:Particle Size; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism; D013499:Surface Properties
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D011804:Quinolines; D020112:Rhodamine 123; C402343:tariquidar; D017239:Paclitaxel