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Optimization of Weight Ratio for DSPE-PEG/TPGS Hybrid Micelles to Improve Drug Retention and Tumor Penetration

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

The optimized DSPE-PEG2000/TPGS micelles could serve as a promising vehicle to improve drug retention and penetration in tumor.

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Abbreviations

ASL:

Asulacrine

ASL-micelles:

Asulacrine micelles

CLSM:

Confocal laser scanning microscope

CMC:

Critical micelle concentration

DL:

Drug loading

DMEM:

Dulbecco’s modified Eagle’s media

ECM:

Extracellular matrix

EE:

Encapsulation efficiency

FBS:

Fetal bovine serum

FITC:

Fluorescein isothiocyanate isomer I

MCTS:

Multicellular tumor spheroids

MTT:

3-(4, 5-Dimethylthia-zol-2-yl) -2, 5-diphenyltetrazolium bromide

PDI:

Polydispersity index

TEM:

Transmission electron microscopy

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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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Author notes

  1. Ya Jin and Zimei Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutics, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People’s Republic of China

    Ya Jin, Caibin Li, Weisai Zhou, Jianping Liu & Wenli Zhang

  2. School of Pharmacy, University of Auckland, Private Bag, Auckland, 92019, New Zealand

    Zimei Wu & John P. Shaw

  3. Auckland Cancer Society Research Centre, University of Auckland, Private Bag, Auckland, 92019, New Zealand

    Bruce C. Baguley

Authors
  1. Ya Jin
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  2. Zimei Wu
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Correspondence to Jianping Liu or Wenli Zhang.

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Jin, Y., Wu, Z., Li, C. et al. Optimization of Weight Ratio for DSPE-PEG/TPGS Hybrid Micelles to Improve Drug Retention and Tumor Penetration. Pharm Res 35, 13 (2018). https://doi.org/10.1007/s11095-017-2340-y

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  • DOI: https://doi.org/10.1007/s11095-017-2340-y

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