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Design, Synthesis, and Evaluation of Original Carriers for Targeting Vascular Endothelial Growth Factor Receptor Interactions

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Purpose

Angiogenesis is a key event in tumor growth and metastasis, chronic inflammatory disease, and cardiovascular disease. It is controlled by positive and negative regulators, which include vascular endothelial growth factor (VEGF) as the most active of these. VEGF/VEGF receptors are important targets not only for therapy but also for imaging. Based on the structural study of VEGF, we developed a novel cyclopeptide (cyclo-VEGI) that exhibits powerful antitumor properties. We herein report the design of novel molecules derived from cyclo-VEGI as potential targeting agents in cancer and other angiogenesis-related diseases.

Methods

We performed selective chemical modification of the most active VEGF-derived cyclopeptide (cyclo-VEGI). Original hydrophilic linkers were synthesized and coupled to cyclo-VEGI. These reactions provide nanocarriers for delivery. The inhibitory effect of the different compounds on VEGF binding was evaluated in competition assays with 125I-VEGF. A fluorescent cyclo-VEGI peptide was synthezised to assess direct binding and internalization of cyclo-VEGI.

Results

Chemical modifications of cyclo-VEGI do not diminish the biological activity of cyclo-VEGI as measured in competition assays; in fact, it is even increased. Moreover there is a strong cellular accumulation of the fluorescent-labeled cyclo-VEGI. Conjugates synthesized in this study may be useful leads to design delivery systems for targeting approaches in cancer and other angiogenesis-related diseases.

Conclusion

The modified cyclo-VEGIs may have a wide range of applications and represent a useful tool to develop delivery/carrier systems for therapeutic targeting or imaging.

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Abbreviations

Abs301:

absorbance at 301 nm

AcOH:

acetic acid

All:

allyl

Boc:

tert-butoxycarbonyl

CHO:

Chinese hamster ovary

cyclo-VEGI:

cyclo-vascular endothelial growth inhibitor

Da:

dalton

DMF:

dimethylformamide

Flt-1:

fms-like tyrosine kinase-1

Fmoc:

9-fluorenylmethoxycarbonyl

HBTU:

2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

HOBt:

hydroxybenzotriazol

KDR:

kinase domain receptor

MALDI:

matrix-assisted laser desorption/ionization

MsCl:

mesyl chloride

NMM:

N-methylmorpholine

NMR:

nuclear magnetic resonance

Pbf:

2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

PhtNK:

potassium phtalimidate

PVDF:

poly(vinylidene difluoride)

SPPS:

solid-phase peptidic synthesis

TEG:

triethyleneglycol

THF:

tetrahydrofuran

Tis:

triisopropylsilane

TsCl:

tosyl chloride

Trt:

trityl

VEGF:

vascular endothelial growth factor

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Acknowledgments

This work was carried out in the frame of a collaboration between Comissariat à l’Energie Atomique (CEA), Bio-Organic Chemistry Group (LRC DSM-98-15, CNRS UMR5084), and INSERM E0113. The authors gratefully acknowledge CEA and Conseil Régional d’Aquitaine for providing financial support through the Ph.D. grant of M. G. This work was supported by grants from the Ligue Nationale contre le Cancer (Comité de la Gironde, G. D.; Equipelabellisée, A. B.), the Conseil Régional d’Aquitaine (G. D., A. B.), and the European Commission (FP6,LSCH-CT-2003-503233, STROMA, to A. B.; “The European Commission is not liable for any use that may be made of the information contained”).

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Authors and Affiliations

  1. CEA Saclay, DSM/DRECAM/LSI/LPI, 91191, Gif-sur-Yvette Cedex, France

    Mario Gonçalves & Natacha Betz

  2. CNRS UMR5084-Chimie Bio-Organic Chemistry Group, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, F-33076, Bordeaux Cedex, France

    Mario Gonçalves, Karine Estieu-Gionnet, Thomas Berthelot, Georges Laïn, Mireille Bayle, Xavier Canron & Gérard Déléris

  3. INSERM E0113-Molecular Angiogenesis Laboratory, Université Bordeaux 1, 33405, Talence, France

    Karine Estieu-Gionnet & Andreas Bikfalvi

Authors
  1. Mario Gonçalves
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  2. Karine Estieu-Gionnet
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  3. Thomas Berthelot
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  4. Georges Laïn
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  5. Mireille Bayle
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  6. Xavier Canron
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  7. Natacha Betz
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  8. Andreas Bikfalvi
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  9. Gérard Déléris
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Correspondence to Gérard Déléris.

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Gonçalves, M., Estieu-Gionnet, K., Berthelot, T. et al. Design, Synthesis, and Evaluation of Original Carriers for Targeting Vascular Endothelial Growth Factor Receptor Interactions. Pharm Res 22, 1411–1421 (2005). https://doi.org/10.1007/s11095-005-5265-9

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  • DOI: https://doi.org/10.1007/s11095-005-5265-9

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