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

Wenwu Xiao, Nianhuan Yao, Li Peng, Ruiwu Liu, Kit Lam

Research output: Contribution to journalArticle

36 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)94-103
Number of pages10
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume36
Issue number1
DOIs
StatePublished - Jan 2009

Fingerprint

Optical Imaging
Glioblastoma
Heterografts
Integrins
Ligands
Cyclic Peptides
temozolomide
Peptide Library
Neoplasms
Streptavidin
Nude Mice
Radiotherapy
Therapeutics
Peptides
Survival
CY5.5 cyanine dye
Antibodies
biotin-streptavidin complex

Keywords

  • Cancer targeting
  • Combinatorial chemistry
  • Glioblastoma
  • Integrin
  • Molecular imaging
  • One-bead one-compound peptide library
  • Optical imaging
  • Small animal imaging

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Near-infrared optical imaging in glioblastoma xenograft with ligand-targeting α3 integrin. / Xiao, Wenwu; Yao, Nianhuan; Peng, Li; Liu, Ruiwu; Lam, Kit.

In: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 36, No. 1, 01.2009, p. 94-103.

Research output: Contribution to journalArticle

@article{8de9cd56ba164ddbab30744da644005b,
title = "Near-infrared optical imaging in glioblastoma xenograft with ligand-targeting α3 integrin",
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.",
keywords = "Cancer targeting, Combinatorial chemistry, Glioblastoma, Integrin, Molecular imaging, One-bead one-compound peptide library, Optical imaging, Small animal imaging",
author = "Wenwu Xiao and Nianhuan Yao and Li Peng and Ruiwu Liu and Kit Lam",
year = "2009",
month = "1",
doi = "10.1007/s00259-008-0920-0",
language = "English (US)",
volume = "36",
pages = "94--103",
journal = "European Journal of Nuclear Medicine and Molecular Imaging",
issn = "1619-7070",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Near-infrared optical imaging in glioblastoma xenograft with ligand-targeting α3 integrin

AU - Xiao, Wenwu

AU - Yao, Nianhuan

AU - Peng, Li

AU - Liu, Ruiwu

AU - Lam, Kit

PY - 2009/1

Y1 - 2009/1

N2 - 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.

AB - 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.

KW - Cancer targeting

KW - Combinatorial chemistry

KW - Glioblastoma

KW - Integrin

KW - Molecular imaging

KW - One-bead one-compound peptide library

KW - Optical imaging

KW - Small animal imaging

UR - http://www.scopus.com/inward/record.url?scp=57249094350&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=57249094350&partnerID=8YFLogxK

U2 - 10.1007/s00259-008-0920-0

DO - 10.1007/s00259-008-0920-0

M3 - Article

C2 - 18712382

AN - SCOPUS:57249094350

VL - 36

SP - 94

EP - 103

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

SN - 1619-7070

IS - 1

ER -