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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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