Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble

Hua Zhang, Sarah Tam, Elizabeth S. Ingham, Lisa M. Mahakian, Chun Yen Lai, Spencer K. Tumbale, Tambet Teesalu, Neil Hubbard, Alexander D Borowsky, Katherine W. Ferrara

Research output: Contribution to journalArticle

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Abstract

Ultrasound molecular imaging has great potential to impact early disease diagnosis, evaluation of disease progression and the development of target-specific therapy. In this paper, two neuropilin-1 (NRP) targeted peptides, CRPPR and ATWLPPR, were conjugated onto the surface of lipid microbubbles (MBs) to evaluate molecular imaging of tumor angiogenesis in a breast cancer model. Development of a molecular imaging agent using CRPPR has particular importance due to the previously demonstrated internalizing capability of this and similar ligands. Invitro, CRPPR MBs bound to an NRP-expressing cell line 2.6 and 15.6 times more than ATWLPPR MBs and non-targeted (NT) MBs, respectively, and the binding was inhibited by pretreating the cells with an NRP antibody. Invivo, the backscattered intensity within the tumor, relative to nearby vasculature, increased over time during the ~6min circulation of the CRPPR-targeted contrast agents providing high contrast images of angiogenic tumors. Approximately 67% of the initial signal from CRPPR MBs remained bound after the majority of circulating MBs had cleared (8min), 8 and 4.5 times greater than ATWLPPR and NT MBs, respectively. Finally, at 7-21 days after the first injection, we found that CRPPR MBs cleared faster from circulation and tumor accumulation was reduced likely due to a complement-mediated recognition of the targeted microbubble and a decrease in angiogenic vasculature, respectively. In summary, we find that CRPPR MBs specifically bind to NRP-expressing cells and provide an effective new agent for molecular imaging of angiogenesis.

Original languageEnglish (US)
Pages (from-to)104-113
Number of pages10
JournalBiomaterials
Volume56
DOIs
StatePublished - Jul 1 2015

Fingerprint

Neuropilin-1
Molecular imaging
Microbubbles
Molecular Imaging
Tumors
Ultrasonography
Ultrasonics
Neoplasms
Antibodies
Lipids
Contrast Media
Peptides
Ligands
Cells
Disease Progression
Early Diagnosis

Keywords

  • Angiogenesis
  • Invivo
  • Microbubble
  • Molecular imaging
  • Peptide
  • Targeting

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

Cite this

Zhang, H., Tam, S., Ingham, E. S., Mahakian, L. M., Lai, C. Y., Tumbale, S. K., ... Ferrara, K. W. (2015). Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble. Biomaterials, 56, 104-113. https://doi.org/10.1016/j.biomaterials.2015.03.043

Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble. / Zhang, Hua; Tam, Sarah; Ingham, Elizabeth S.; Mahakian, Lisa M.; Lai, Chun Yen; Tumbale, Spencer K.; Teesalu, Tambet; Hubbard, Neil; Borowsky, Alexander D; Ferrara, Katherine W.

In: Biomaterials, Vol. 56, 01.07.2015, p. 104-113.

Research output: Contribution to journalArticle

Zhang, H, Tam, S, Ingham, ES, Mahakian, LM, Lai, CY, Tumbale, SK, Teesalu, T, Hubbard, N, Borowsky, AD & Ferrara, KW 2015, 'Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble', Biomaterials, vol. 56, pp. 104-113. https://doi.org/10.1016/j.biomaterials.2015.03.043
Zhang, Hua ; Tam, Sarah ; Ingham, Elizabeth S. ; Mahakian, Lisa M. ; Lai, Chun Yen ; Tumbale, Spencer K. ; Teesalu, Tambet ; Hubbard, Neil ; Borowsky, Alexander D ; Ferrara, Katherine W. / Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble. In: Biomaterials. 2015 ; Vol. 56. pp. 104-113.
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