Synthesis and comparative evaluation of novel (64)Cu-labeled high affinity cell-specific peptides for positron emission tomography imaging of tumor vasculature

Joseph R Merrill; Krzysztof Krajewski; Hong Yuan; Jonathan E Frank; David S Lalush; Cam Patterson; Anka N Veleva

doi:10.1016/j.biomaterials.2016.01.031

Synthesis and comparative evaluation of novel (64)Cu-labeled high affinity cell-specific peptides for positron emission tomography imaging of tumor vasculature

Biomaterials. 2016 Apr:84:241-249. doi: 10.1016/j.biomaterials.2016.01.031. Epub 2016 Jan 21.

Authors

Joseph R Merrill¹, Krzysztof Krajewski², Hong Yuan³, Jonathan E Frank⁴, David S Lalush⁵, Cam Patterson⁶, Anka N Veleva⁷

Affiliations

¹ Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
² Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
³ Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
⁴ Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
⁵ Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Biomedical Engineering, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: [email protected].
⁶ NewYork Presbyterian Hospital, Weill Cornell Medical Center, New York, NY 10065, USA. Electronic address: [email protected].
⁷ Department of Biomedical Engineering, North Carolina State University, Raleigh, NC 27695, USA; Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, NC 27695, USA. Electronic address: [email protected].

PMID: 26839954
DOI: 10.1016/j.biomaterials.2016.01.031

Abstract

Tumor angiogenesis, the formation of new tumor blood supply, has been recognized as a hallmark of cancer and represents an important target for clinical management of various angiogenesis-dependent solid tumors. Previously, by screening a bacteriophage peptide library we have discovered the FHT-peptide sequence that binds specifically to bone marrow-derived tumor vasculature with high affinity. Here in an effort to determine the potential of the FHT-peptide for in vivo positron emission tomography (PET) imaging of aggressive tumor vasculature we studied four FHT-derivatives: NOTA-FHT, NOTA-(FHT)2, NOTA-PEG-FHT, and NOTA-PEG-(FHT)2. These peptide analogs were synthesized, labeled with the PET radionuclide (64)Cu, and characterized side-by-side with small animal PET and computed tomography imaging (microPET/CT) at 1 h, 4 h, and 24 h post injection in a subcutaneous Lewis lung carcinoma (LLC) tumor model. Because of its excellent in vivo kinetic properties and high tumor-to-background ratio, the (64)Cu-NOTA-FHT radiopeptide was selected for more detailed evaluation. Blocking studies with excess of unlabeled peptide showed specific and peptide mediated (64)Cu-NOTA-FHT tumor uptake. Biodistribution experiments in the same tumor model confirmed microPET/CT imaging results. Human radiation absorbed dose extrapolated from rodent biodistribution of (64)Cu-NOTA-FHT revealed favorable dosimetry profile. The findings from this investigation warrant further development of (64)Cu-NOTA-FHT as a potential targeted diagnostic radiopharmaceutical for PET imaging of aggressive tumor vasculature.

Keywords: (64)Cu-labeled cell-specific peptides; Diagnostic PET radiopharmaceuticals; Molecular imaging; Radiation absorbed dose; Tumor angiogenesis.

Publication types

Comparative Study
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line, Tumor
Copper Radioisotopes / chemistry*
Dose-Response Relationship, Radiation
Female
Humans
Isotope Labeling
Mice, Inbred C57BL
Neoplasms / blood supply*
Neoplasms / diagnostic imaging*
Peptides / chemical synthesis*
Peptides / chemistry
Positron-Emission Tomography / methods*
Radiation Dosage
Tissue Distribution
Tomography, X-Ray Computed

Substances

Copper Radioisotopes
Peptides