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Reversion of Multidrug Resistance by Co-Encapsulation of Doxorubicin and Metformin in Poly(lactide-co-glycolide)-d-α-tocopheryl Polyethylene Glycol 1000 Succinate Nanoparticles

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Abstract

Purpose

P-glycoprotein (P-gp) mediated multidrug resistance (MDR) has been recognized as the main obstacle against successful cancer treatment. To address this problem, co-encapsulated doxorubicin (DOX) and metformin (Met) in a biodegradable polymer composed of poly(lactide-co-glycolide) (PLGA) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared. We reported in our previous study that Met inhibits P-gp in DOX resistant breast cancer (MCF-7/DOX) cells. TPGS is a bioactive compound which has also been shown to inhibit P-gp, further to its pharmaceutical advantages.

Methods

The DOX/Met loaded PLGA-TPGS nanoparticles (NPs) were prepared by double emulsion method and characterized for their surface morphology, size and size distribution, and encapsulation efficiencies of drugs in NPs.

Results

All NPs were found to be spherical-shaped with the size distribution below 100 nm and encapsulation efficiencies were 42.26 ± 2.14% for DOX and 7.04 ± 0.52% for Met. Dual drug loaded NPs showed higher cytotoxicity and apoptosis in MCF-7/DOX cells in comparison to corresponding free drugs. The higher cytotoxicity of dual drug loaded NPs was attributed to the enhanced intracellular drug accumulation due to enhanced cellular uptake and reduced drug efflux which was obtained by combined effects of Met and TPGS in reducing cellular ATP content and inhibiting P-gp.

Conclusion

Simultaneous delivery of DOX and Met via PLGA-TPGS NPs would be a promising approach to overcome MDR in breast cancer chemotherapy.

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Abbreviations

ANOVA:

Analysis of Variance

DCM:

Dichlromethane

DMSO:

Dimethyl Solfoxide

DOX:

Doxorubicin

FBS:

Fetal Bovine Serum

FITC:

Fluorescein Isothiocyanate

MDR:

Multidrug resistance

Met:

Metformin

MFI:

Mean Fluorescence Intensity

mTOR:

Mammalian Target of Rapamycin

PBS:

Phosphate-Buffered Saline

PI:

Propidium Iodide

PI3K:

Phosphatidylinositol 3-Kinases

PLGA:

Poly(lactide-co-glycolide) acetate

Rho123:

Rhodamine 123

TPGS:

D-α-tocopheryl polyethylene glycol 1000 succinate

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Acknowledgments and Disclosures

Authors would like to thank Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran for supporting this project (Grant No 5/104/991). The authors declare that they have no conflict of interests regarding the publication of this article, financial and/or otherwise.

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Authors and Affiliations

  1. Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Vahid Shafiei-Irannejad & Nosratollah Zarghami

  2. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Vahid Shafiei-Irannejad, Nasser Samadi, Roya Salehi, Bahman Yousefi, Mahdi Rahimi & Abolfazl Akbarzadeh

  3. Departement of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Vahid Shafiei-Irannejad, Nasser Samadi, Bahman Yousefi & Nosratollah Zarghami

  4. Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Roya Salehi, Mahdi Rahimi & Abolfazl Akbarzadeh

  5. Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran

    Nosratollah Zarghami

Authors
  1. Vahid Shafiei-Irannejad
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  2. Nasser Samadi
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  3. Roya Salehi
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  4. Bahman Yousefi
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  7. Nosratollah Zarghami
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Correspondence to Nosratollah Zarghami.

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Shafiei-Irannejad, V., Samadi, N., Salehi, R. et al. Reversion of Multidrug Resistance by Co-Encapsulation of Doxorubicin and Metformin in Poly(lactide-co-glycolide)-d-α-tocopheryl Polyethylene Glycol 1000 Succinate Nanoparticles. Pharm Res 35, 119 (2018). https://doi.org/10.1007/s11095-018-2404-7

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  • DOI: https://doi.org/10.1007/s11095-018-2404-7

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