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Polymeric Micelles of PEG-PLA Copolymer as a Carrier for Salinomycin Against Gemcitabine-Resistant Pancreatic Cancer

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ABSTRACT

Purpose

Resistance to gemcitabine in pancreatic cancer (PC) may account for the failure of conventional treatments. Recently, salinomycin (SAL) has been identified as selective inhibitor of cancer stem cells (CSCs). In our study, we aimed to deliver SAL to gemcitabine-resistant PC by the aid of poly ethylene glycol-b-poly lactic acid (PEG-b-PLA) polymeric micelles (PMs).

Methods

SAL-loaded PMs were prepared and investigated in terms of pharmaceutical properties. MTT and Annexin V/PI assays were used to study cell proliferation and apoptosis in AsPC-1 cells in response to treatment with SAL micellar formulations. Alterations in CSC phenotype, invasion strength, and mRNA expression of epithelial mesenchymal transition (EMT) markers were also determined in the treated cells. In vivo antitumor study was performed in Balb/c AsPC-1 xenograft mice.

Results

PM formulations of SAL were prepared in suitable size and loading traits. In gemcitabine-resistant AsPC-1 cells, SAL was found to significantly increase cell mortality and apoptosis. It was also observed that SAL micellar formulations inhibited invasion and harnessed EMT in spite of induced expression of Snail. The in vivo antitumor experiment showed significant tumor eradication and the highest survival probability in mice treated with SAL PMs.

Conclusions

The obtained results showed the efficacy of SAL nano-formulation against PC tumor cells.

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Abbreviations

CMC:

Critical micelle concentration

CSCs:

Cancer stem cells

DLS:

Dynamic light scattering

EE:

Entrapment efficiency

EMT:

Epithelial to mesenchymal transition

EPR:

Enhanced permeability and retention

FBS:

Fetal bovine serum

HPLC:

High performance liquid chromatography

IC50% :

50% inhibitory concentration

LD:

Loading density

MTT:

3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl tetrazolium bromide

NP:

Nanoparticle

PBS:

Phosphate buffered saline

PC:

Pancreatic cancer

PDI:

Polydispersity index

PEG-b-PLA:

Poly ethylene glycol-b-poly lactic acid

PI:

Propidium iodide

PMs:

Polymeric micelles

RT-PCR:

Real-time polymerase chain reaction

SAL:

Salinomycin

TEM:

Transmission electron microscopy

THF:

Tetrahydrofuran

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ACKNOWLEDGMENTS AND DISCLOSURES

We would like to express our profound thanks to Dr. Babak Paknejad for his assistance in animal experiments. This work is a part of the PhD project of first author and was financially supported by a grant numbered 91-03-33-19300 from Tehran University of Medical Sciences and Health Services.

Author information

Authors and Affiliations

  1. Aerosol Research Laboratory, Department of Pharmaceutics, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Zahra Daman & Kambiz Gilani

  2. Department of Molecular Biology, Pasteur Institute of Iran, Tehran, Iran

    Hamed Montazeri

  3. Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran

    Masoumeh Azizi & Faegheh Rezaie

  4. Department of Toxicology-Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Seyed Nasser Ostad

  5. Department of Medicinal Chemistry, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Mohsen Amini

  6. Medicinal Plants Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Kambiz Gilani

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  1. Zahra Daman
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  2. Hamed Montazeri
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  3. Masoumeh Azizi
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  4. Faegheh Rezaie
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  7. Kambiz Gilani
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Correspondence to Kambiz Gilani.

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Daman, Z., Montazeri, H., Azizi, M. et al. Polymeric Micelles of PEG-PLA Copolymer as a Carrier for Salinomycin Against Gemcitabine-Resistant Pancreatic Cancer. Pharm Res 32, 3756–3767 (2015). https://doi.org/10.1007/s11095-015-1737-8

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  • DOI: https://doi.org/10.1007/s11095-015-1737-8

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