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A Molecular Imaging Paradigm to Rapidly Profile Response to Angiogenesis-directed Therapy in Small Animals

Abstract

Purpose

The development of novel angiogenesis-directed therapeutics is hampered by the lack of non-invasive imaging metrics capable of assessing treatment response. We report the development and validation of a novel molecular imaging paradigm to rapidly assess response to angiogenesis-directed therapeutics in preclinical animal models.

Procedures

A monoclonal antibody-based optical imaging probe targeting vascular endothelial growth factor receptor-2 (VEGFR2) expression was synthesized and evaluated in vitro and in vivo via multispectral fluorescence imaging.

Results

The optical imaging agent demonstrated specificity for the target receptor in cultured endothelial cells and in vivo. The agent exhibited significant accumulation within 4T1 xenograft tumors. Mice bearing 4T1 xenografts and treated with sunitinib exhibited both tumor growth arrest and decreased accumulation of NIR800-αVEGFR2ab compared to untreated cohorts (p = 0.0021).

Conclusions

Molecular imaging of VEGFR2 expression is a promising non-invasive biomarker for assessing angiogenesis and evaluating the efficacy of angiogenesis-directed therapies.

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Acknowledgements

The authors wish to acknowledge contributions from Zou Yue for assistance with tumor implantation and the Vanderbilt University Immunohistochemistry Core laboratory for IHC staining. The authors thank Frank Revetta for helpful discussions regarding the IHC. The authors acknowledge pilot funding (HCM) from the Vanderbilt Special Program of Research Excellence (SPORE) in Breast Cancer (P50 CA098131) and additional NIH research support from a post-doctoral training grant in imaging science (T32 EB003817, JCG) and the NCI-funded South-Eastern Center for small animal imaging (U24 CA 126588, JCG). HCM is supported by a Career Development Award from the NCI (K25 CA127349).

Author information

Correspondence to H. Charles Manning.

Electronic Supplementary Material

Below is the link to the electronic supplementary materials.

Supplementary Fig. 1
figure6

Tumor size and NIR800-αVEGFR2ab fluorescence (tumor relative to the contralateral hind limb) of animals treated with an imaging dose of NIR800-αVEGFR2ab 5 days prior (n = 9) and animals naïve to NIR800-αVEGFR2ab exposure (n = 10) (GIF 212 KB).

Supplementary Fig. 2
figure7

a Tumor size versus fluorescence intensity from NIR800-αVEGFR2ab accumulation in the tumor normalized to the contralateral hind limb for vehicle-treated animals. b Tumor size versus morphometric analysis of VEGFR2 expression after vehicle treatment (GIF 232 KB).

High resolution image (TIFF 67.2 KB)

High resolution image (TIFF 68.3 KB)

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Virostko, J., Xie, J., Hallahan, D.E. et al. A Molecular Imaging Paradigm to Rapidly Profile Response to Angiogenesis-directed Therapy in Small Animals. Mol Imaging Biol 11, 204–212 (2009). https://doi.org/10.1007/s11307-008-0193-9

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Key words

  • Molecular imaging
  • Biomarker
  • VEGFR2
  • Sunitinib
  • Angiogenesis
  • Optical imaging
  • Multispectral fluorescence
  • Near-infrared fluorescence
  • Tyrosine kinase inhibitor
  • VEGF