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Improving Plasma Stability and Bioavailability In Vivo of Gemcitabine Via Nanoparticles of mPEG-PLG-GEM Complexed with Calcium Phosphate

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Abstract

Purpose

Despite being widely used for the treatment of several solid tumors, Gemcitabine (GEM) exhibits several suboptimal pharmacokinetic properties. Therefore, the design of nanoparticle delivery systems is a promising strategy to enhance GEM pharmacokinetic properties.

Methods

In this work, the polymeric material methoxy poly(ethylene glycol)-block-poly(L-glutamic acid)-graft-gemcitabine (mPEG-b-PLG-g-GEM) was synthesized through the covalent conjugation of GEM with the carboxylic group of methoxy poly(ethylene glycol)-block-poly (L-glutamic acid) (mPEG-b-PLG) (mPEG113, Mn = 5000). mPEG-PLG-GEM/CaP nanoparticles were prepared through the simple mixing of calcium and phosphate/mPEG-PLG-GEM solutions. mPEG-PLG-GEM was embedded in the calcium phophate (CaP) backbone via electrostatic interactions.

Results

After incubation in plasma at 37°C for 24 h, gemcitabine was degraded by 24.6% for the mPEG-PLG-GEM, 14.7% for the mPEG-PLG-GEM/CaP nanoparticles, and 90% for the free gemcitabine solution. It was observed that mPEG-PLG-GEM and mPEG-PLG-GEM/CaP improved the area-under-curve (AUC) values by 5.26-fold and 6.33-fold compared to free drug, respectively.

Conclusion

The amide bond linked gemcitabine polymers was able to protect GEM from cytidine deaminase degradation in vivo, and the skeleton formed by the calcium phosphate enhanced the stability and prolonged the half-life of GEM. Importantly, mPEG-PLG-GEM/CaP nanoparticles elevated the GEM plasma concentration in an animal model.

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Abbreviations

CDA:

Cytidine deaminase

dCK:

Deoxycytidine kinase

dCTD:

Deoxycytidylate deaminase

dFdC:

Difluorodeoxycytidine

dFdCTP:

Deoxycytidine 5′-triphosphate

dFdU:

Diflurodeoxyuridine

dFdUMP:

Di-fluorodeoxyuridine monophosphate

DLC:

Drug loading content

DLS:

Dynamic laser light scattering

EDS:

Energy Dispersive Spectroscopy

FT-IR:

Fourier transform infrared spectroscopy

HPLC:

High Performance Liquid Chromatography

IR:

Infrared Radiation

LC / MS:

Liquid chromatography-mass spectrometry

PK:

Pharmacokinetics

PLG-g-mPEG:

Poly(Lglutamic acid)-g-methoxy poly(ethylene glycol) copolymer

PBS:

Phosphate buffered saline

TEM:

Transmission electron microscopy

UV-Vis:

Ultra-violet-visible

XRD:

X-ray Diffraction

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ACKNOWLEDGMENTS AND DISCLOSURES

We sincerely thank Amanda Pearce for the linguistic assistance during the revision of this manuscript.

Funding

This work was supported by the Financial Grant from China Postdoctoral Science Foundation (2016 M600216) and Foundation of Shenyang Pharmaceutical University (ZQN2016008).

Author information

Authors and Affiliations

  1. Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China

    Wei Chu, Pengqian Tian, Ning Ding, Qing Cai, Jinlong Li, Xuezhi Zhuo, Jingxin Gou, Yu Zhang, Haibing He & Xing Tang

  2. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, People’s Republic of China

    Zhaohui Tang

  3. Department of Functional food and Wine, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China

    Tian Yin

Authors
  1. Wei Chu
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  2. Pengqian Tian
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  5. Jinlong Li
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  9. Tian Yin
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Correspondence to Xing Tang.

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Chu, W., Tian, P., Ding, N. et al. Improving Plasma Stability and Bioavailability In Vivo of Gemcitabine Via Nanoparticles of mPEG-PLG-GEM Complexed with Calcium Phosphate. Pharm Res 35, 230 (2018). https://doi.org/10.1007/s11095-018-2506-2

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  • DOI: https://doi.org/10.1007/s11095-018-2506-2

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