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Dual In Vivo Quantification of Integrin-targeted and Protease-activated Agents in Cancer Using Fluorescence Molecular Tomography (FMT)

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Abstract

Purpose

Integrins, especially αvβ3 and αvβ5, are upregulated in tumor cells and activated endothelial cells and as such, serve as cancer biomarkers. We developed a novel near-infrared-labeled optical agent for the in vivo detection and quantification of αvβ3/αvβ5.

Procedures

A small peptidomimetic αvβ3 antagonist was synthesized, coupled to a near-infrared fluorescent (NIRF) dye, and tested for binding specificity using integrin-overexpressing cells, inhibition of vitronectin-mediated cell attachment, binding to tumor and endothelial cells in vitro, and competition studies. Pharmacokinetics, biodistribution, specificity of tumor targeting, and the effect of an antiangiogenic treatment were assessed in vivo.

Results

The integrin NIRF agent showed strong selectivity towards αvβ3/αvβ5 in vitro and predominant tumor distribution in vivo, allowing noninvasive and real-time quantification of integrin signal in tumors. Antiangiogenic treatment significantly inhibited integrin signal in vivo but had no effect on a cathepsin-cleavable NIR agent. Simultaneous imaging revealed different patterns of distribution reflecting the underlying differences in integrin and cathepsin biology during tumor progression.

Conclusions

NIRF-labeled integrin antagonists allow noninvasive molecular fluorescent imaging and quantification of tumors in vivo, improving and providing more refined approaches for cancer detection and treatment monitoring.

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Authors and Affiliations

  1. VisEn Medical, Bedford, MA, USA

    Sylvie Kossodo, Chiara Buono, Guojie Ho, Agnieszka Blusztajn, Garry Cuneo, Jun Zhang, Jayme Jensen, Milind Rajopadhye, Wael Yared & Jeffrey Peterson

  2. Merck Research Laboratories, West Point, PA, USA

    Maureen Pickarski, Shu-An Lin, Alexa Gleason, Renee Gaspar, Richard Hargreaves, Paul Coleman, George Hartman, Le Thi Duong, Cyrille Sur & Bohumil Bednar

Authors
  1. Sylvie Kossodo
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  2. Maureen Pickarski
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  3. Shu-An Lin
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  4. Alexa Gleason
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  5. Renee Gaspar
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  6. Chiara Buono
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  7. Guojie Ho
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  8. Agnieszka Blusztajn
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  9. Garry Cuneo
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  10. Jun Zhang
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  11. Jayme Jensen
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  12. Richard Hargreaves
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  13. Paul Coleman
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  14. George Hartman
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  16. Le Thi Duong
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  17. Cyrille Sur
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  18. Wael Yared
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  19. Jeffrey Peterson
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  20. Bohumil Bednar
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Corresponding author

Correspondence to Sylvie Kossodo.

Additional information

This study conclusively establishes for the first time the ability to simultaneously and noninvasively quantify integrin αvβ3 and cathepsin activity using near-infrared fluorescence tomography in vivo.

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Kossodo, S., Pickarski, M., Lin, SA. et al. Dual In Vivo Quantification of Integrin-targeted and Protease-activated Agents in Cancer Using Fluorescence Molecular Tomography (FMT). Mol Imaging Biol 12, 488–499 (2010). https://doi.org/10.1007/s11307-009-0279-z

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  • DOI: https://doi.org/10.1007/s11307-009-0279-z

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