A Smart Paclitaxel-Disulfiram Nanococrystals for Efficient MDR Reversal and Enhanced Apoptosis
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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 β-lactoglobulin (β-LG), with the aim to reverse MDR and therefore enhnce cytotoxicity towards Taxol-resistant A549 cells (A549/TAX).
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.
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.
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.
Keywordsapoptosis combined therapy multidrug resistance nanosuspensions p-glycoprotein
Sensitive human lung adenocarcinoma cell line
Taxol resistant human lung adenocarcinoma cell line
Confocal laser scanning microscope
Dynamic light scattering
Dose reduction index
Fetal bovine serum
Food and Drug administration
High-performance liquid chromatography
Half maximal inhibitory concentration
Multidrug resistance gene-1
3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide
Phosphate buffer saline
Free Paclitaxel-Disulfiram formulation
- PTX-DSF Ns
Powder X-ray Diffraction
Real time quantitative PCR
Scanning electron microscopy
Transmission electron microscopy
Acknowledgments and Disclosures
This study was supported by grants from the National Natural Science Foundation of China (Nos. 81673377, 81473152, and 81402869), the Natural Science Foundation of Jiangsu Province (No. BK20140671), and the Fostering Plan of University Scientific and Technological Innovation Team and Key Members of the Outstanding Young Teacher of Jiangsu Qing Lan Project (2014 and 2016). We also thank Xiaonan Ma, Minhui Sun and Yingjian Hou from the Cellular and Molecular Biology Center of China Pharmaceutical University for providing technical assistance. The authors report no conflicts of interest with this work.
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