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Synthesis and In Vitro Evaluation of Polyethylene Glycol-Paclitaxel Conjugates for Lung Cancer Therapy

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Abstract

Purpose

Pulmonary drug delivery is considered an attractive route of drug administration for lung cancer chemotherapy. However, fast clearance mechanisms result in short residence time of small molecule drugs in the lung. Therefore, achieving a sustained presence of chemotherapeutics in the lung is very challenging. In this study, we synthesized two different polyethylene glycol-paclitaxel ester conjugates with molecular weights of 6 and 20 kDa in order to achieve sustained release of paclitaxel in the lung.

Methods

One structure was synthesized with azide linker using “click” chemistry and the other structure was synthesized with a succinic spacer. The physicochemical and biological properties of the conjugates were characterized in vitro.

Results

Conjugation to polyethylene glycol improved the solubility of paclitaxel by up to four orders of magnitude. The conjugates showed good stability in phosphate buffer saline pH 6.9 (half-life ≥72 h) and in bronchoalveolar lavage (half-life of 3 to 9 h) at both molecular weights, but hydrolyzed quickly in mouse serum (half-life of 1 to 3 h). The conjugates showed cytotoxicity to B16-F10 melanoma cells and LL/2 Lewis lung cancer cells but less than free paclitaxel or Taxol, the commercial paclitaxel formulation.

Conclusions

These properties imply that the conjugates have the potential to retain paclitaxel in the lung for a prolonged duration and to sustain its release locally for a better efficacy.

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Abbreviations

BAL:

Bronchoalveolar lavage

DIC:

N,N’-Diisopropylcarbodiimide

DMAP:

4-Dimethylaminopyridine

DMEM:

Dulbecco’s modified eagle medium

DMF:

Dimethylformamide

DMSO:

Dimethyl sulfoxide

DPBS:

Dulbecco’s phosphate-buffered saline

FBS:

Fetal bovine serum

FT-IR:

Fourier transform infrared spectroscopy

HBSS:

Hank’s balanced salt solution

HPLC:

High performance liquid chromatography

MEM-Alpha:

Minimum essential medium eagle alpha

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide

MW:

Molecular weight

NMR:

Nuclear magnetic resonance

PEG:

Polyethylene glycol

PTX:

Paclitaxel

R.T.:

Room temperature

t ½ :

Half-life

TEA:

Triethylamine

TLC:

Thin layer chromatography

TOF-ES-MS:

Time-of-flight electrospray mass spectrometry

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was a thesis project funded by the European Commission, Education, Audiovisual and Culture Executive Agency (EACEA), Erasmus Mundus programme, NanoFar doctorate. This work was also supported by the Fonds de la Recherche Scientifique Médicale, Belgium (Grant 3.4503.12). Rita Vanbever is Maître de Recherches of the Fonds National de la Recherche Scientifique (Belgium). The author would like to thank Dr. Cecil Le Duff, Department of chemistry, Université catholique de Louvain, for helping with detection and analysis of NMR data.

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Authors and Affiliations

  1. Advanced Drug Delivery & Biomaterials, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E. Mounier, 73, 1200, Brussels, Belgium

    Tian Luo, Véronique Préat & Rita Vanbever

  2. School of Pharmacy, University of Nottingham, Nottingham, UK

    Tian Luo, Johannes Magnusson, Cameron Alexander & Cynthia Bosquillon

  3. Medicinal Chemistry, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium

    Raphael Frédérick

Authors
  1. Tian Luo
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  2. Johannes Magnusson
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  3. Véronique Préat
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  4. Raphael Frédérick
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  5. Cameron Alexander
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  6. Cynthia Bosquillon
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  7. Rita Vanbever
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Correspondence to Rita Vanbever.

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Luo, T., Magnusson, J., Préat, V. et al. Synthesis and In Vitro Evaluation of Polyethylene Glycol-Paclitaxel Conjugates for Lung Cancer Therapy. Pharm Res 33, 1671–1681 (2016). https://doi.org/10.1007/s11095-016-1908-2

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  • DOI: https://doi.org/10.1007/s11095-016-1908-2

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