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Near-infrared optical imaging in glioblastoma xenograft with ligand-targeting α3 integrin

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Patients with glioblastoma usually have a very poor prognosis. Even with a combination of radiotherapy plus temozolomide, the median survival of these patients is only 14.6 months. New treatment approaches to this cancer are needed. Our purpose is to develop new cell surface-binding ligands for glioblastoma cells and use them as targeted imaging and therapeutic agents for this deadly disease.

Methods

One-bead one-compound combinatorial cyclic peptide libraries were screened with live human glioblastoma U-87MG cells. The binding affinity and targeting specificity of peptides identified were tested with in vitro experiments on cells and in vivo and ex vivo experiments on U-87MG xenograft mouse model.

Results

A cyclic peptide, LXY1, was identified and shown to be binding to the α3 integrin of U-87MG cells with moderately high affinity (K d = 0.5 ± 0.1 μM) and high specificity. Biotinylated LXY1, when complexed with streptavidin–Cy5.5 (SA–Cy5.5) conjugate, targeted both subcutaneous and orthotopic U-87MG xenograft implants in nude mice. The in vivo targeting specificity was further verified by strong inhibition of tumor uptake of LXY1–biotin–SA–Cy5.5 complex when intravenously injecting the animals with anti-α3 integrin antibody or excess unlabeled LXY1 prior to administrating the imaging probe. The smaller univalent LXY1–Cy5.5 conjugate (2,279 Da) was found to have a faster accumulation in the U-87MG tumor and shorter retention time compared with the larger tetravalent LXY1–biotin–SA–Cy5.5 complex (approximately 64 kDa).

Conclusions

Collectively, the data reveals that LXY1 has the potential to be developed into an effective imaging and therapeutic targeting agent for human glioblastoma.

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Abbreviations

c:

d-cysteine

B:

l-hydroxyl-proline

X:

random amino acids

Hci:

homocitrulline

HOBt:

1-hydroxybenzotriazole

DIC:

1,3-diisopropylcarbodiimide

TFA:

trifluoroacetic acid

TIS:

triisopropylsilane

EDTA:

ethylenediaminetetraacetic acid

PE:

phycoerythrin

DAPI:

4′,6-diamidino-2-phenylindole

IACUC:

Institutional Animal Care and Use Committee

FBS:

fetal bovine serum

PBS:

phosphate-buffered saline

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Acknowledgments

This work was supported by the National Institutes of Health (R33CA-86364, R33CA-99136, U19CA113298, and P50CA097257). We would like to thank Ms. Mary Saunders and Mr. Joel Kugelmass for the editorial assistance.

Conflict of interest

There is no conflict of interest for this manuscript.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Cancer Center, University of California Davis, 4501 X Street, Sacramento, CA, 95817, USA

    Wenwu Xiao, Nianhuan Yao, Li Peng, Ruiwu Liu & Kit S. Lam

Authors
  1. Wenwu Xiao
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  2. Nianhuan Yao
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  3. Li Peng
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  4. Ruiwu Liu
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  5. Kit S. Lam
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Corresponding author

Correspondence to Kit S. Lam.

Additional information

Standard single letter amino acids are used for all natural l-amino acids.

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Xiao, W., Yao, N., Peng, L. et al. Near-infrared optical imaging in glioblastoma xenograft with ligand-targeting α3 integrin. Eur J Nucl Med Mol Imaging 36, 94–103 (2009). https://doi.org/10.1007/s00259-008-0920-0

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  • DOI: https://doi.org/10.1007/s00259-008-0920-0

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