Journal
PHARMACEUTICAL RESEARCH
Volume 35, Issue 4, Pages -Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-018-2370-0
Keywords
apoptosis; combined therapy; multidrug resistance; nanosuspensions; p-glycoprotein
Funding
- National Natural Science Foundation of China [81673377, 81473152, 81402869]
- Natural Science Foundation of Jiangsu Province [BK20140671]
- Fostering Plan of University Scientific and Technological Innovation Team and Key Members of the Outstanding Young Teacher of Jiangsu Qing Lan Project
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Purpose A multidrug resistance (MDR) modulator, disulfiram (DSF), was incorporated into pure paclitaxel (PTX) nanoparticles to construct a smart paclitaxel-disulfiram nanococrystals (PTX-DSF Ns) stabilized by beta-lactoglobulin (beta-LG), with the aim to reverse MDR and therefore enhnce cytotoxicity towards Taxol-resistant A549 cells (A549/TAX). Method PTX-DSF Ns was prepared by antisolvent precipitation method. Flow cytometry was used to determine the cell uptake, drug efflux inhibition, cell cycle phase arrest and apoptosis. MDR-1 gene expression level was detected by real time quantitative PCR and gel electrophoresis. Results PTX-DSF Ns prepared from the optimized formulation had an optimum diameter of 160 nm, was stable and had a high drug-loading capacity. Importantly, the uptake of PTX-DSF Ns in A549/TAX cells was 14-fold greater than the uptake of PTX Ns. Furthermore, PTX-DSF Ns promoted 5-folds increase in apoptosis, enabled 7-folds reduction in the IC50, and rendered 8.9-fold decrease in the dose compared with free PTX. Conclusion PTX-DSF Ns with a precise mass ratio offer efficient cytotoxicity against Taxol-resistant cells and a novel approach for codelivery and sensitizing MDR cancer to chemotherapy. In addition, the use of nanosuspensions as a combined treatment provides a new research avenue for nanosuspensions.
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