Targeting activated platelets: A unique and potentially universal approach for cancer imaging

May Lin Yap, James D. McFadyen, Xiaowei Wang, Nicholas A. Zia, Jan David Hohmann, Melanie Ziegler, Yu Yao, Alan Pham, Matthew Harris, Paul S. Donnelly, P. Mark Hogarth, Geoffrey A. Pietersz, Bock Lim, Karlheinz Peter

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer. Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64Cu or ultrasound-enhancing microbubbles. Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells. Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma. Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities. The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease. Conclusion Our study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets. We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities. These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach.

Original languageEnglish
Pages (from-to)2565-2574
Number of pages10
JournalTheranostics
Volume7
Issue number10
DOIs
Publication statusPublished - 2017

Keywords

  • Activated platelets
  • Cancer
  • Fluorescence imaging
  • PET
  • Ultrasound

Cite this

Yap, May Lin ; McFadyen, James D. ; Wang, Xiaowei ; Zia, Nicholas A. ; Hohmann, Jan David ; Ziegler, Melanie ; Yao, Yu ; Pham, Alan ; Harris, Matthew ; Donnelly, Paul S. ; Hogarth, P. Mark ; Pietersz, Geoffrey A. ; Lim, Bock ; Peter, Karlheinz. / Targeting activated platelets : A unique and potentially universal approach for cancer imaging. In: Theranostics. 2017 ; Vol. 7, No. 10. pp. 2565-2574.
@article{8941ca69d6f94a9580697701627312c2,
title = "Targeting activated platelets: A unique and potentially universal approach for cancer imaging",
abstract = "Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer. Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64Cu or ultrasound-enhancing microbubbles. Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells. Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma. Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities. The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease. Conclusion Our study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets. We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities. These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach.",
keywords = "Activated platelets, Cancer, Fluorescence imaging, PET, Ultrasound",
author = "Yap, {May Lin} and McFadyen, {James D.} and Xiaowei Wang and Zia, {Nicholas A.} and Hohmann, {Jan David} and Melanie Ziegler and Yu Yao and Alan Pham and Matthew Harris and Donnelly, {Paul S.} and Hogarth, {P. Mark} and Pietersz, {Geoffrey A.} and Bock Lim and Karlheinz Peter",
year = "2017",
doi = "10.7150/thno.19900",
language = "English",
volume = "7",
pages = "2565--2574",
journal = "Theranostics",
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Yap, ML, McFadyen, JD, Wang, X, Zia, NA, Hohmann, JD, Ziegler, M, Yao, Y, Pham, A, Harris, M, Donnelly, PS, Hogarth, PM, Pietersz, GA, Lim, B & Peter, K 2017, 'Targeting activated platelets: A unique and potentially universal approach for cancer imaging' Theranostics, vol. 7, no. 10, pp. 2565-2574. https://doi.org/10.7150/thno.19900

Targeting activated platelets : A unique and potentially universal approach for cancer imaging. / Yap, May Lin; McFadyen, James D.; Wang, Xiaowei; Zia, Nicholas A.; Hohmann, Jan David; Ziegler, Melanie; Yao, Yu; Pham, Alan; Harris, Matthew; Donnelly, Paul S.; Hogarth, P. Mark; Pietersz, Geoffrey A.; Lim, Bock; Peter, Karlheinz.

In: Theranostics, Vol. 7, No. 10, 2017, p. 2565-2574.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Targeting activated platelets

T2 - A unique and potentially universal approach for cancer imaging

AU - Yap, May Lin

AU - McFadyen, James D.

AU - Wang, Xiaowei

AU - Zia, Nicholas A.

AU - Hohmann, Jan David

AU - Ziegler, Melanie

AU - Yao, Yu

AU - Pham, Alan

AU - Harris, Matthew

AU - Donnelly, Paul S.

AU - Hogarth, P. Mark

AU - Pietersz, Geoffrey A.

AU - Lim, Bock

AU - Peter, Karlheinz

PY - 2017

Y1 - 2017

N2 - Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer. Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64Cu or ultrasound-enhancing microbubbles. Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells. Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma. Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities. The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease. Conclusion Our study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets. We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities. These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach.

AB - Rationale The early detection of primary tumours and metastatic disease is vital for successful therapy and is contingent upon highly specific molecular markers and sensitive, non-invasive imaging techniques. We hypothesized that the accumulation of activated platelets within tumours is a general phenomenon and thus represents a novel means for the molecular imaging of cancer. Here we investigate a unique single chain antibody (scFv), which specifically targets activated platelets, as a novel biotechnological tool for molecular imaging of cancer. Methods The scFvGPIIb/IIIa, which binds specifically to the activated form of the platelet integrin receptor GPIIb/IIIa present on activated platelets, was conjugated to either Cy7, 64Cu or ultrasound-enhancing microbubbles. Using the Cy7 labelled scFvGPIIb/IIIa, fluorescence imaging was performed in mice bearing four different human tumour xenograft models; SKBr3, MDA-MB-231, Ramos and HT-1080 cells. Molecular imaging via PET and ultrasound was performed using the scFvGPIIb/IIIa-64Cu and scFvGPIIb/IIIa-microbubbles, respectively, to further confirm specific targeting of scFvGPIIb/IIIa to activated platelets in the tumour stroma. Results Using scFvGPIIb/IIIa we successfully showed specific targeting of activated platelets within the microenvironment of human tumour xenografts models via three different molecular imaging modalities. The presence of platelets within the tumour microenvironment, and as such their relevance as a molecular target epitope in cancer was further confirmed via immunofluorescence of human tumour sections of various cancer types, thus validating the translational importance of our novel approach to human disease. Conclusion Our study provides proof of concept for imaging and localization of tumours by molecular targeting activated platelets. We illustrate the utility of a unique scFv as a versatile biotechnological tool which can be conjugated to various contrast agents for molecular imaging of cancer using three different imaging modalities. These findings warrant further development of this activated platelet specific scFvGPIIb/IIIa, potentially as a universal marker for cancer diagnosis and ultimately for drug delivery in an innovative theranostic approach.

KW - Activated platelets

KW - Cancer

KW - Fluorescence imaging

KW - PET

KW - Ultrasound

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