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Title: A Radiofluorinated Divalent Cystine Knot Peptide for Tumor PET Imaging

A divalent knottin containing two separate integrin binding epitopes (RGD) in the adjacent loops, 3-4A, was recently developed and reported in our previous publication. In the current study, 3-4A was radiofluorinated with a 4-nitrophenyl 2- 18F-fluoropropinate ( 18F-NFP) group and the resulting divalent positron emission tomography (PET) probe, 18F-FP–3-4A, was evaluated as a novel imaging probe to detect integrin αvβ3 positive tumors in living animals. Knottin 3-4A was synthesized by solid phase peptide synthesis, folded, and site-specifically conjugated with 18/19F-NFP to produce the fluorinated peptide 18/19F-fluoropropinate-3-4A ( 18/19F-FP–3-4A). The stability of 18F-FP–3-4A was tested in both phosphate buffered saline (PBS) buffer and mouse serum. Cell uptake assays of the radiolabeled peptides were performed using U87MG cells. In addition, small animal PET imaging and biodistribution studies of 18F-FP–3-4A were performed in U87MG tumor-bearing mice. The receptor targeting specificity of the radiolabeled peptide was also verified by coinjecting the probe with a blocking peptide cyclo(RGDyK). Our study showed that 18F-FP–3-4A exhibited excellent stability in PBS buffer (pH 7.4) and mouse serum. Small animal PET imaging and biodistribution data revealed that 18F-FP–3-4A exhibited rapid and good tumor uptake (3.76 ± 0.59% ID/g and 2.22 ± 0.62% ID/g at 0.5 and 1 h, respectively).more » 18F-FP–3-4A was rapidly cleared from the normal tissues, resulting in excellent tumor-to-normal tissue contrasts. For example, liver uptake was only 0.39 ± 0.07% ID/g and the tumor to liver ratio was 5.69 at 1 h p.i. Furthermore, coinjection of cyclo(RGDyK) with 18F-FP–3-4A significantly inhibited tumor uptake (0.41 ± 0.12 vs 1.02 ± 0.19% ID/g at 2.5 h) in U87MG xenograft models, demonstrating specific accumulation of the probe in the tumor. In summary, the divalent probe 18F-FP–3-4A is characterized by rapid and high tumor uptake and excellent tumor-to-normal tissue ratios. 18F-FP–3-4A is a highly promising knottin based PET probe for translating into clinical imaging of tumor angiogenesis.« less
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [3] ;  [2] ;  [2]
  1. Fudan University, Shanghai (China). Department of Nuclear Medicine, Zhongshan Hospital; Stanford Univ., CA (United States). Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Canary Center at Stanford for Cancer Early Detection
  2. Stanford Univ., CA (United States). Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Canary Center at Stanford for Cancer Early Detection
  3. Fudan University, Shanghai (China). Department of Nuclear Medicine, Zhongshan Hospita
Publication Date:
Grant/Contract Number:
SC0008397
Type:
Accepted Manuscript
Journal Name:
Molecular Pharmaceutics
Additional Journal Information:
Journal Volume: 11; Journal Issue: 11; Journal ID: ISSN 1543-8384
Publisher:
American Chemical Society (ACS)
Research Org:
Stanford Univ., CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; 18F; cystine-knot peptide; divalent; integrin αvβ3; PET
OSTI Identifier:
1440564

Jiang, Lei, Kimura, Richard H., Ma, Xiaowei, Tu, Yingfeng, Miao, Zheng, Shen, Bin, Chin, Frederick T., Shi, Hongcheng, Gambhir, Sanjiv Sam, and Cheng, Zhen. A Radiofluorinated Divalent Cystine Knot Peptide for Tumor PET Imaging. United States: N. p., Web. doi:10.1021/mp500018s.
Jiang, Lei, Kimura, Richard H., Ma, Xiaowei, Tu, Yingfeng, Miao, Zheng, Shen, Bin, Chin, Frederick T., Shi, Hongcheng, Gambhir, Sanjiv Sam, & Cheng, Zhen. A Radiofluorinated Divalent Cystine Knot Peptide for Tumor PET Imaging. United States. doi:10.1021/mp500018s.
Jiang, Lei, Kimura, Richard H., Ma, Xiaowei, Tu, Yingfeng, Miao, Zheng, Shen, Bin, Chin, Frederick T., Shi, Hongcheng, Gambhir, Sanjiv Sam, and Cheng, Zhen. 2014. "A Radiofluorinated Divalent Cystine Knot Peptide for Tumor PET Imaging". United States. doi:10.1021/mp500018s. https://www.osti.gov/servlets/purl/1440564.
@article{osti_1440564,
title = {A Radiofluorinated Divalent Cystine Knot Peptide for Tumor PET Imaging},
author = {Jiang, Lei and Kimura, Richard H. and Ma, Xiaowei and Tu, Yingfeng and Miao, Zheng and Shen, Bin and Chin, Frederick T. and Shi, Hongcheng and Gambhir, Sanjiv Sam and Cheng, Zhen},
abstractNote = {A divalent knottin containing two separate integrin binding epitopes (RGD) in the adjacent loops, 3-4A, was recently developed and reported in our previous publication. In the current study, 3-4A was radiofluorinated with a 4-nitrophenyl 2-18F-fluoropropinate (18F-NFP) group and the resulting divalent positron emission tomography (PET) probe, 18F-FP–3-4A, was evaluated as a novel imaging probe to detect integrin αvβ3 positive tumors in living animals. Knottin 3-4A was synthesized by solid phase peptide synthesis, folded, and site-specifically conjugated with 18/19F-NFP to produce the fluorinated peptide 18/19F-fluoropropinate-3-4A (18/19F-FP–3-4A). The stability of 18F-FP–3-4A was tested in both phosphate buffered saline (PBS) buffer and mouse serum. Cell uptake assays of the radiolabeled peptides were performed using U87MG cells. In addition, small animal PET imaging and biodistribution studies of 18F-FP–3-4A were performed in U87MG tumor-bearing mice. The receptor targeting specificity of the radiolabeled peptide was also verified by coinjecting the probe with a blocking peptide cyclo(RGDyK). Our study showed that 18F-FP–3-4A exhibited excellent stability in PBS buffer (pH 7.4) and mouse serum. Small animal PET imaging and biodistribution data revealed that 18F-FP–3-4A exhibited rapid and good tumor uptake (3.76 ± 0.59% ID/g and 2.22 ± 0.62% ID/g at 0.5 and 1 h, respectively). 18F-FP–3-4A was rapidly cleared from the normal tissues, resulting in excellent tumor-to-normal tissue contrasts. For example, liver uptake was only 0.39 ± 0.07% ID/g and the tumor to liver ratio was 5.69 at 1 h p.i. Furthermore, coinjection of cyclo(RGDyK) with 18F-FP–3-4A significantly inhibited tumor uptake (0.41 ± 0.12 vs 1.02 ± 0.19% ID/g at 2.5 h) in U87MG xenograft models, demonstrating specific accumulation of the probe in the tumor. In summary, the divalent probe 18F-FP–3-4A is characterized by rapid and high tumor uptake and excellent tumor-to-normal tissue ratios. 18F-FP–3-4A is a highly promising knottin based PET probe for translating into clinical imaging of tumor angiogenesis.},
doi = {10.1021/mp500018s},
journal = {Molecular Pharmaceutics},
number = 11,
volume = 11,
place = {United States},
year = {2014},
month = {4}
}