Ciclosporin A as a Reversal Agent Against Concurrent Multidrug Resistance in Tumors with Nanobubbles.

Abstract

The purpose of this work was to challenge the multidrug resistance (MDR) in tumor through nanobubbles (NB) co-loaded reversal agent and chemotherapeutic drug layer by layer. The core/shell NB structure contains Doxorubicin (Dox) as anticancer drug in the core and Ciclosporin A (CsA), a cyclic polypeptide composed of 11 amino acids, as a reversal agent in the shell. The drug was designed to work against concurrent MDR processes and was defined as CsA/Dox/NB. HL60/ADM cells with typical high expression of multidrug resistance associated protein 1 (MRP1) were assessed by flow cytometer, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and Western blot analysis to observe the in vitro and in vivo anticancer efficacy and reversal ability of MDR. Results demonstrated that the function and expression of MRP1 could be successfully inhibited by CsA as a reversal agent from the pharmaceutical preparation, leading to dramatic increase of intracellular concentration of Dox. The accumulation of anticancer drug in the MDR cancer cells enhanced inhibition of cell proliferation through G2/M arrest and tumor growth of nude mice xenograft model. It was therefore concluded that the CsA/Dox/NB can be a promising drug candidate in overcoming tumor MDR.