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Development of Long-Circulating pH-Sensitive Liposomes to Circumvent Gemcitabine Resistance in Pancreatic Cancer Cells

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Abstract

Purposes

To develop pH-sensitive liposomes (PSL) containing a high content of gemcitabine; and to investigate whether drug loading (DL) would alter the in vitro and pharmacokinetic properties.

Methods

PSL with a high DL were obtained using a modified small-volume incubation method. The DL effects on drug release rate and in vitro cytotoxicity of PSL were evaluated using MIA PaCa-2 pancreatic cancer cells and their pharmacokinetics investigated in rats.

Results

The highest DL of 4.5 ± 0.1% was achieved for gemcitabine in PSL with 145 ± 5 nm diameter. DL did not alter the in vitro release rate from PSL. The IC50 (48 h) of PSL (DL 0.5 and 4.5%) and non pH-sensitive liposomes (NPSL, DL 4.2%) were 1.1 ± 0.1, 0.7 ± 0.1 and 37.0 ± 7.5 μM, respectively. The PSL resulted in a 4.2-fold increase in its elimination half-life (6.2 h) compared to gemcitabine solution (1.4 h) in rats. No significant difference in pharmacokinetic parameters was observed between the two PSL (DL 0.5 and 4.5%).

Conclusion

The PSL offered advantages over NPSL in restoring the sensitivity of pancreatic cancer cells to gemcitabine without requiring a high DL. DL in the PSL did not alter release rate, cytotoxicity or their long-circulating properties.

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Abbreviations

ABC transporters:

ATP-binding cassette transporters

CHEMS:

Cholesterylhemisuccinate

DL:

Drug loading

DOPE:

1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

EE:

Entrapment efficiency

EPR:

Enhanced permeability and retention

IC50 :

the drug concentration causing 50% inhibition

MDR:

Multi-drug resistance

NPSL:

Non pH-sensitive liposomes

PC:

Pancreatic cancer

PDI:

Polydispersity index

PEG:

Polyethylene glycol

PSL:

pH-sensitive liposomes

RES:

Reticuloendothelial system

SVI:

Small volume incubation

TEM:

Transmission electron microscopy

TFHE:

Thin-film hydration extrusion

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ACKNOWLEDGMENTS AND DISCLOSURES

The financial support for this study was provided by a Marsden Fund by the Royal Society of New Zealand (Grant number UOA1201) and an Auckland Medical Research Fund (Grant Number 1113026). We also thank Mr Alan Gall from VJU for his technical support with the animal studies. Hongtao Xu also wishes to acknowledge the support of a Doctorial Scholarship provided by The University of Auckland, New Zealand.

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Authors and Affiliations

  1. School of Pharmacy, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Hongtao Xu & Zimei Wu

  2. Department of Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    James W. Paxton

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  1. Hongtao Xu
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  2. James W. Paxton
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  3. Zimei Wu
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Correspondence to Zimei Wu.

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Xu, H., Paxton, J.W. & Wu, Z. Development of Long-Circulating pH-Sensitive Liposomes to Circumvent Gemcitabine Resistance in Pancreatic Cancer Cells. Pharm Res 33, 1628–1637 (2016). https://doi.org/10.1007/s11095-016-1902-8

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  • DOI: https://doi.org/10.1007/s11095-016-1902-8

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