In vivo, dual-modality OCT/LIF imaging using a novel VEGF receptor-targeted NIR fluorescent probe in the AOM-treated mouse model

Amy M. Winkler, Photini F S Rice, Jan Weichsel, Jennifer M. Watson, Marina V. Backer, Joseph M. Backer, Jennifer K Barton

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Purpose: Increased vascular endothelial growth factor (VEGF) receptor expression has been found at the sites of angiogenesis, particularly in tumor growth areas, as compared with quiescent vasculature. An increase in VEGF receptor-2 is associated with colon cancer progression. The in vivo detection of VEGF receptor is of interest for the purposes of studying basic mechanisms of carcinogenesis, making clinical diagnoses, and monitoring the efficacy of chemopreventive and therapeutic agents. In this study, a novel single chain (sc)VEGF-based molecular probe is utilized in the azoxymethane (AOM)-treated mouse model of colorectal cancer to study delivery route and specificity for disease. Procedures: The probe was constructed by site-specific conjugation of a near-infrared fluorescent dye, Cy5.5, to scVEGF and detected in vivo with a dual-modality optical coherence tomography/ laser-induced fluorescence (OCT/LIF) endoscopic system. A probe inactivated via excessive biotinylation was utilized as a control for nonreceptor-mediated binding. The LIF excitation source was a 633-nm He:Ne laser, and red/near-infrared fluorescence was detected with a spectrometer. OCT was used to obtain two-dimensional longitudinal tomograms at eight rotations in the distal colon. Fluorescence emission levels were correlated with OCT-detected disease in vivo. OCTdetected disease was verified with hematoxylin and eosin stained histology slides ex vivo. Results: High fluorescence emission intensity from the targeted probe was correlated with tumor presence as detected using OCT in vivo and VEGFR-2 immunostaining on histological sections ex vivo. The inactivated probe accumulated preferentially on the surface of tumor lesions and in lymphoid aggregate tissue and was less selective for VEGFR-2. Conclusion: The scVEGF/Cy probe delivered via colonic lavage reaches tumor vasculature and selectively accumulates in VEGFR-2-positive areas, resulting in high sensitivity and specificity for tumor detection. The combination of OCT and LIF imaging modalities may allow the simultaneous study of tumor morphology and protein expression for the development of diagnostic and therapeutic methods for colorectal cancer.

Original languageEnglish (US)
Pages (from-to)1173-1182
Number of pages10
JournalMolecular Imaging and Biology
Volume13
Issue number6
DOIs
StatePublished - Dec 2011

Fingerprint

Azoxymethane
Vascular Endothelial Growth Factor Receptor
Optical Imaging
Optical Coherence Tomography
Fluorescent Dyes
Vascular Endothelial Growth Factor Receptor-2
Lasers
Fluorescence
Neoplasms
Colorectal Neoplasms
Biotinylation
Molecular Probes
Therapeutic Irrigation
Lymphoid Tissue
Hematoxylin
Eosine Yellowish-(YS)
Colonic Neoplasms
Vascular Endothelial Growth Factor A
Histology
Colon

Keywords

  • Angiogenesis
  • Colon cancer
  • Laser-induced fluorescence
  • Molecular imaging
  • Optical coherence tomography
  • Vascular endothelial growth factor receptor

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Radiology Nuclear Medicine and imaging

Cite this

In vivo, dual-modality OCT/LIF imaging using a novel VEGF receptor-targeted NIR fluorescent probe in the AOM-treated mouse model. / Winkler, Amy M.; Rice, Photini F S; Weichsel, Jan; Watson, Jennifer M.; Backer, Marina V.; Backer, Joseph M.; Barton, Jennifer K.

In: Molecular Imaging and Biology, Vol. 13, No. 6, 12.2011, p. 1173-1182.

Research output: Contribution to journalArticle

Winkler, Amy M. ; Rice, Photini F S ; Weichsel, Jan ; Watson, Jennifer M. ; Backer, Marina V. ; Backer, Joseph M. ; Barton, Jennifer K. / In vivo, dual-modality OCT/LIF imaging using a novel VEGF receptor-targeted NIR fluorescent probe in the AOM-treated mouse model. In: Molecular Imaging and Biology. 2011 ; Vol. 13, No. 6. pp. 1173-1182.
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AU - Watson, Jennifer M.

AU - Backer, Marina V.

AU - Backer, Joseph M.

AU - Barton, Jennifer K

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AB - Purpose: Increased vascular endothelial growth factor (VEGF) receptor expression has been found at the sites of angiogenesis, particularly in tumor growth areas, as compared with quiescent vasculature. An increase in VEGF receptor-2 is associated with colon cancer progression. The in vivo detection of VEGF receptor is of interest for the purposes of studying basic mechanisms of carcinogenesis, making clinical diagnoses, and monitoring the efficacy of chemopreventive and therapeutic agents. In this study, a novel single chain (sc)VEGF-based molecular probe is utilized in the azoxymethane (AOM)-treated mouse model of colorectal cancer to study delivery route and specificity for disease. Procedures: The probe was constructed by site-specific conjugation of a near-infrared fluorescent dye, Cy5.5, to scVEGF and detected in vivo with a dual-modality optical coherence tomography/ laser-induced fluorescence (OCT/LIF) endoscopic system. A probe inactivated via excessive biotinylation was utilized as a control for nonreceptor-mediated binding. The LIF excitation source was a 633-nm He:Ne laser, and red/near-infrared fluorescence was detected with a spectrometer. OCT was used to obtain two-dimensional longitudinal tomograms at eight rotations in the distal colon. Fluorescence emission levels were correlated with OCT-detected disease in vivo. OCTdetected disease was verified with hematoxylin and eosin stained histology slides ex vivo. Results: High fluorescence emission intensity from the targeted probe was correlated with tumor presence as detected using OCT in vivo and VEGFR-2 immunostaining on histological sections ex vivo. The inactivated probe accumulated preferentially on the surface of tumor lesions and in lymphoid aggregate tissue and was less selective for VEGFR-2. Conclusion: The scVEGF/Cy probe delivered via colonic lavage reaches tumor vasculature and selectively accumulates in VEGFR-2-positive areas, resulting in high sensitivity and specificity for tumor detection. The combination of OCT and LIF imaging modalities may allow the simultaneous study of tumor morphology and protein expression for the development of diagnostic and therapeutic methods for colorectal cancer.

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KW - Laser-induced fluorescence

KW - Molecular imaging

KW - Optical coherence tomography

KW - Vascular endothelial growth factor receptor

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