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A Bioengineered Peptide that Localizes to and Illuminates Medulloblastoma: A New Tool with Potential for Fluorescence-Guided Surgical Resection



Abstract

Tumors of the central nervous system are challenging to treat due to the limited effectiveness and associated toxicities of chemotherapy and radiation therapy. For tumors that can be removed surgically, extent of malignant tissue resection has been shown to correlate with disease progression, recurrence, and survival. Thus, improved technologies for real-time brain tumor imaging are critically needed as tools for guided surgical resection. We previously engineered a novel peptide that binds with high affinity and unique specificity to αVβ3, αVβ5, and α5β1 integrins, which are present on tumor cells, and the vasculature of many cancers, including brain tumors. In the current study, we conjugated this engineered peptide to a near infrared fluorescent dye (Alexa Fluor 680), and used the resulting molecular probe for non-invasive whole body imaging of patient-derived medulloblastoma xenograft tumors implanted in the cerebellum of mice. The engineered peptide exhibited robust targeting and illumination of intracranial medulloblastoma following both intravenous and intraperitoneal injection routes. In contrast, a variant of the engineered peptide containing a scrambled integrin-binding sequence did not localize to brain tumors, demonstrating that tumor-targeting is driven by specific integrin interactions. Ex vivo imaging was used to confirm the presence of tumor and molecular probe localization to the cerebellar region. These results warrant further clinical development of the engineered peptide as a tool for image-guided resection of central nervous system tumors. 



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Original article
peer-reviewed

A Bioengineered Peptide that Localizes to and Illuminates Medulloblastoma: A New Tool with Potential for Fluorescence-Guided Surgical Resection


Author Information

Shelley E. Ackerman

Department of Bioengineering, Stanford University

Christy M. Wilson

School of Medicine, Stanford University

Suzana A. Kahn

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine

James R. Kintzing

Department of Bioengineering, Stanford University

Darren A. Jindal

Department of Bioengineering, Stanford University

Samuel H. Cheshier

Department of Neurosurgery and Neurology, Stanford University School of Medicine & Lucile Packard Children's Hospital

Gerald A. Grant

Department of Neurosurgery, Stanford University School of Medicine

Jennifer R. Cochran Corresponding Author

Department of Bioengineering and (by courtesy) Chemical Engineering, Stanford University


Ethics Statement and Conflict of Interest Disclosures

Human subjects: Consent was obtained by all participants in this study. Stanford University Research Compliance Office - Administrative Panel on Human Subjects in Medical Research issued approval Protocol ID #: 12625
IRB #: 4593 (Panel: 5). Animal subjects: Stanford University Administrative Panel on Laboratory Animal Care (APLAC) Issued protocol number APLAC #28701 and APLAC #26548. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Stanford Center for Children’s Brain Tumors at Lucile Packard Children’s Hospital, the Stanford Bio-X Program, Stanford Child Health Research Institute, NIH/NIDNS 1K08NS075144-01, and Stanford Bioengineering REU Program for funding to support this project. Fellowship support from the following sources is acknowledged: Stanford Bioengineering and Stanford Bio-X Bowes Graduate Fellowship Programs (S.E.A.), PEW Charitable Trusts (S.A.K.) and National Science Foundation Graduate Fellowship (J.R.K.). . Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Intellectual property info: The authors (S.E.A. and J.R.C.) are listed as inventors on pending and issued patent applications related to technology described in this work. . Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Acknowledgements

All in vivo imaging was conducted in the Stanford Small Animal Imaging Facility with the assistance of Dr. Timothy C. Doyle, and tissue sectioning and staining was performed in the Stanford University Department of Comparative Medicine’s Histology Lab. The authors wish to thank Dr. Nicolas V. Currier and Dr. Michael S. B. Edwards for helpful discussions, and the Stanford Center for Children’s Brain Tumors at Lucile Packard Children’s Hospital, the Stanford Bio-X Program, Stanford Child Health Research Institute, NIH/NIDNS 1K08NS075144-01, and Stanford Bioengineering REU Program for funding to support this project. Fellowship support from the following sources is acknowledged: Stanford Bioengineering and Stanford Bio-X Bowes Graduate Fellowship Programs (S.E.A.), PEW Charitable Trusts (S.A.K.) and National Science Foundation Graduate Fellowship (J.R.K.).


Original article
peer-reviewed

A Bioengineered Peptide that Localizes to and Illuminates Medulloblastoma: A New Tool with Potential for Fluorescence-Guided Surgical Resection


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Original article
peer-reviewed
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Intraoperative Fluorescence Research

A Bioengineered Peptide that Localizes to and Illuminates Medulloblastoma: A New Tool with Potential for Fluorescence-Guided Surgical Resection

Shelley E. Ackerman">Shelley E. Ackerman, Christy M. Wilson">Christy M. Wilson, Suzana A. Kahn">Suzana A. Kahn, James R. Kintzing">James R. Kintzing, Darren A. Jindal">Darren A. Jindal, Samuel H. Cheshier">Samuel H. Cheshier, Gerald A. Grant">Gerald A. Grant, Jennifer R. Cochran">Jennifer R. Cochran

  • Author Information
    Shelley E. Ackerman

    Department of Bioengineering, Stanford University

    Christy M. Wilson

    School of Medicine, Stanford University

    Suzana A. Kahn

    Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine

    James R. Kintzing

    Department of Bioengineering, Stanford University

    Darren A. Jindal

    Department of Bioengineering, Stanford University

    Samuel H. Cheshier

    Department of Neurosurgery and Neurology, Stanford University School of Medicine & Lucile Packard Children's Hospital

    Gerald A. Grant

    Department of Neurosurgery, Stanford University School of Medicine

    Jennifer R. Cochran Corresponding Author

    Department of Bioengineering and (by courtesy) Chemical Engineering, Stanford University


    Ethics Statement and Conflict of Interest Disclosures

    Human subjects: Consent was obtained by all participants in this study. Stanford University Research Compliance Office - Administrative Panel on Human Subjects in Medical Research issued approval Protocol ID #: 12625
    IRB #: 4593 (Panel: 5). Animal subjects: Stanford University Administrative Panel on Laboratory Animal Care (APLAC) Issued protocol number APLAC #28701 and APLAC #26548. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Stanford Center for Children’s Brain Tumors at Lucile Packard Children’s Hospital, the Stanford Bio-X Program, Stanford Child Health Research Institute, NIH/NIDNS 1K08NS075144-01, and Stanford Bioengineering REU Program for funding to support this project. Fellowship support from the following sources is acknowledged: Stanford Bioengineering and Stanford Bio-X Bowes Graduate Fellowship Programs (S.E.A.), PEW Charitable Trusts (S.A.K.) and National Science Foundation Graduate Fellowship (J.R.K.). . Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Intellectual property info: The authors (S.E.A. and J.R.C.) are listed as inventors on pending and issued patent applications related to technology described in this work. . Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

    Acknowledgements

    All in vivo imaging was conducted in the Stanford Small Animal Imaging Facility with the assistance of Dr. Timothy C. Doyle, and tissue sectioning and staining was performed in the Stanford University Department of Comparative Medicine’s Histology Lab. The authors wish to thank Dr. Nicolas V. Currier and Dr. Michael S. B. Edwards for helpful discussions, and the Stanford Center for Children’s Brain Tumors at Lucile Packard Children’s Hospital, the Stanford Bio-X Program, Stanford Child Health Research Institute, NIH/NIDNS 1K08NS075144-01, and Stanford Bioengineering REU Program for funding to support this project. Fellowship support from the following sources is acknowledged: Stanford Bioengineering and Stanford Bio-X Bowes Graduate Fellowship Programs (S.E.A.), PEW Charitable Trusts (S.A.K.) and National Science Foundation Graduate Fellowship (J.R.K.).


    Article Information

    Published: September 17, 2014

    DOI

    10.7759/cureus.207

    Cite this article as:

    Ackerman S E, Wilson C M, Kahn S A, et al. (September 17, 2014) A Bioengineered Peptide that Localizes to and Illuminates Medulloblastoma: A New Tool with Potential for Fluorescence-Guided Surgical Resection . Cureus 6(9): e207. doi:10.7759/cureus.207

    Publication history

    Received by Cureus: August 29, 2014
    Peer review began: August 31, 2014
    Peer review concluded: September 17, 2014
    Published: September 17, 2014

    Copyright

    © Copyright 2014
    Ackerman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 3.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    License

    This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Tumors of the central nervous system are challenging to treat due to the limited effectiveness and associated toxicities of chemotherapy and radiation therapy. For tumors that can be removed surgically, extent of malignant tissue resection has been shown to correlate with disease progression, recurrence, and survival. Thus, improved technologies for real-time brain tumor imaging are critically needed as tools for guided surgical resection. We previously engineered a novel peptide that binds with high affinity and unique specificity to αVβ3, αVβ5, and α5β1 integrins, which are present on tumor cells, and the vasculature of many cancers, including brain tumors. In the current study, we conjugated this engineered peptide to a near infrared fluorescent dye (Alexa Fluor 680), and used the resulting molecular probe for non-invasive whole body imaging of patient-derived medulloblastoma xenograft tumors implanted in the cerebellum of mice. The engineered peptide exhibited robust targeting and illumination of intracranial medulloblastoma following both intravenous and intraperitoneal injection routes. In contrast, a variant of the engineered peptide containing a scrambled integrin-binding sequence did not localize to brain tumors, demonstrating that tumor-targeting is driven by specific integrin interactions. Ex vivo imaging was used to confirm the presence of tumor and molecular probe localization to the cerebellar region. These results warrant further clinical development of the engineered peptide as a tool for image-guided resection of central nervous system tumors. 



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Shelley E. Ackerman

Department of Bioengineering, Stanford University

Christy M. Wilson

School of Medicine, Stanford University

Suzana A. Kahn

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine

James R. Kintzing

Department of Bioengineering, Stanford University

Darren A. Jindal

Department of Bioengineering, Stanford University

Samuel H. Cheshier, M.D.

Department of Neurosurgery and Neurology, Stanford University School of Medicine & Lucile Packard Children's Hospital

Gerald A. Grant

Department of Neurosurgery, Stanford University School of Medicine

Jennifer R. Cochran

Department of Bioengineering and (by courtesy) Chemical Engineering, Stanford University

For correspondence:
jennifer.cochran@stanford.edu

Shelley E. Ackerman

Department of Bioengineering, Stanford University

Christy M. Wilson

School of Medicine, Stanford University

Suzana A. Kahn

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine

James R. Kintzing

Department of Bioengineering, Stanford University

Darren A. Jindal

Department of Bioengineering, Stanford University

Samuel H. Cheshier, M.D.

Department of Neurosurgery and Neurology, Stanford University School of Medicine & Lucile Packard Children's Hospital

Gerald A. Grant

Department of Neurosurgery, Stanford University School of Medicine

Jennifer R. Cochran

Department of Bioengineering and (by courtesy) Chemical Engineering, Stanford University

For correspondence:
jennifer.cochran@stanford.edu