Optimization of Weight Ratio for DSPE-PEG/TPGS Hybrid Micelles to Improve Drug Retention and Tumor Penetration
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To enhance therapeutic efficacy and prevent phlebitis caused by Asulacrine (ASL) precipitation post intravenous injection, ASL-loaded hybrid micelles with size below 40 nm were developed to improve drug retention and tumor penetration.
ASL-micelles were prepared using different weight ratios of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethyleneglycol-2000 (DSPE-PEG2000) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymers. Stability of micelles was optimized in terms of critical micelle concentration (CMC) and drug release properties. The encapsulation efficiency (EE) and drug loading were determined using an established dialysis-mathematic fitting method. Multicellular spheroids (MCTS) penetration and cytotoxicity were investigated on MCF-7 cell line. Pharmacokinetics of ASL-micelles was evaluated in rats with ASL-solution as control.
The ASL-micelles prepared with DSPE-PEG2000 and TPGS (1:1, w/w) exhibited small size (~18.5 nm), higher EE (~94.12%), better sustained in vitro drug release with lower CMC which may be ascribed to the interaction between drug and carriers. Compared to free ASL, ASL-micelles showed better MCTS penetration capacity and more potent cytotoxicity. Pharmacokinetic studies demonstrated that the half-life and AUC values of ASL-micelles were approximately 1.37-fold and 3.49-fold greater than that of free ASL.
The optimized DSPE-PEG2000/TPGS micelles could serve as a promising vehicle to improve drug retention and penetration in tumor.
KEY WORDSasulacrine CMC drug retention hybrid micelles multicellular spheroids penetration
Confocal laser scanning microscope
Critical micelle concentration
Dulbecco’s modified Eagle’s media
Fetal bovine serum
Fluorescein isothiocyanate isomer I
Multicellular tumor spheroids
3-(4, 5-Dimethylthia-zol-2-yl) -2, 5-diphenyltetrazolium bromide
Transmission electron microscopy
ACKNOWLEDGMENTS AND DISCLOSURES
This study was financially supported by the National Science Foundation Grant of China (No. 81503005), the Natural Science Fundation of Jiangsu Province (No. BK20140669), the Priority Academic Program Development of Jiangsu Higher Education Institutions, and National Science and Technology Major Project (No. 2017YFA0205400). The authors declare no competing financial interest.
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