Synthesis and evaluation of an18F-labeled derivative of F3 for targeting surface-expressed nucleolin in cancer and tumor endothelial cells.
The surface overexpression of nucleolin provides an anchor for the specific attachment of biomolecules to cancer and angiogenic endothelial cells. The peptide F3 is a high-affinity ligand of the nucleolin receptor (NR) that has been investigated as a carrier to deliver biologically active molecules to tumors for both therapeutic and imaging applications. A site-specific PEGylated F3 derivative was radiolabeled with [18F]Al-F. The binding affinity and cellular distribution of the compound was assessed in tumor (H2N) and tumor endothelial (2H-11) cells. Specific uptake via the NR was demonstrated by the siRNA knockdown of nucleolin in both cell lines. The partition and the plasma stability of the compound were assessed at 37°C. The enzyme-mediated site-specific modification of F3 to give NODA-PEG-F3 (NP-F3) was achieved. Radiolabeling with [18F]Al-F gave18F-NP-F3.18F-NP-F3 demonstrated high affinity for cancer and tumor endothelial cells. The siRNA knockdown of nucleolin resulted in a binding affinity reduction of 50% to 60%, confirming cell surface binding via the NR. NP-F3 was stable in serum for 2 h.18F-NP-F3 is reported as the first18F-labeled F3 derivative. It was obtained in a site-specific, high-yield, and efficient manner and binds to surface NR in the low nanomolar range, suggesting it has potential as a tumor and angiogenesis tracer.
Department of Oncology, CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
Phoebe Y H
PY
Lam
Department of Oncology, CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
Christopher R T
CR
Hillyar
Department of Oncology, CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK.
Sarah
S
Able
Department of Oncology, CR-UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, UK. katherine.vallis@oncology.ox.ac.uk.
Katherine A
KA
Vallis
D000595:Amino Acid Sequence; D001667:Binding, Competitive; D001692:Biological Transport; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D042783:Endothelial Cells / Q000378:metabolism*; D005462:Fluorine Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D010750:Phosphoproteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014018:Tissue Distribution; D000097796:Nucleolin
D005462:Fluorine Radioisotopes; D007205:Indium Radioisotopes; D010455:Peptides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin
F3; [18F]Al-F; endothelial cells; nucleolin receptor; transglutaminase