Abstract
Contrast enhanced MRI is commonly used in imaging and treatment planning of prostate cancer. However, no tumor targeting contrast agent is commercially available for accurate detection and characterization of prostate cancer with MRI. Extradomain B fibronectin (EDB-FN), an oncoprotein present in aggressive tumors, is a promising molecular target for detection and stratification of high-risk prostate cancer. In this work, we have identified four small peptides (GVK, IGK, SGV, and ZD2) specific to EDB-FN for tumor targeting. In silico simulations of the binding patterns and affinities of peptides to the EDB protein fragment revealed different binding site to different peptide in the ligand-receptor interactions. Tumor specificity and organ distribution of the peptides were assessed using fluorescence imaging in male mice bearing PC-3 human prostate cancer xenografts. Targeted contrast agents were synthesized by conjugating tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the peptides in the solid phase, followed by complexation with GdCl3. The contrast agents were characterized by MALDI-TOF mass spectrometry and relaxivity measurements. All four peptide Gd-DOTA conjugates resulted in robust tumor contrast enhancement in MR imaging of the PC3 mouse prostate cancer model. The peptide Gd-DOTA conjugates specific to EDB-FN are promising targeted small molecular macrocyclic contrast agents for MR molecular imaging of prostate cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3906-3915 |
| Number of pages | 10 |
| Journal | Molecular Pharmaceutics |
| Volume | 14 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 6 2017 |
| Externally published | Yes |
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Keywords
- EDB fibronectin
- MRI
- peptide
- prostate cancer
- targeted contrast agent
ASJC Scopus subject areas
- Molecular Medicine
- Pharmaceutical Science
- Drug Discovery
Cite this
Synthesis and Assessment of Peptide Gd-DOTA Conjugates Targeting Extradomain B Fibronectin for Magnetic Resonance Molecular Imaging of Prostate Cancer. / Li, Yajuan; Han, Zheng; Roelle, Sarah; DeSanto, Aidan; Sabatelle, Rob; Schur, Rebecca; Lu, Zheng Rong.
In: Molecular Pharmaceutics, Vol. 14, No. 11, 06.11.2017, p. 3906-3915.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis and Assessment of Peptide Gd-DOTA Conjugates Targeting Extradomain B Fibronectin for Magnetic Resonance Molecular Imaging of Prostate Cancer
AU - Li, Yajuan
AU - Han, Zheng
AU - Roelle, Sarah
AU - DeSanto, Aidan
AU - Sabatelle, Rob
AU - Schur, Rebecca
AU - Lu, Zheng Rong
PY - 2017/11/6
Y1 - 2017/11/6
N2 - Contrast enhanced MRI is commonly used in imaging and treatment planning of prostate cancer. However, no tumor targeting contrast agent is commercially available for accurate detection and characterization of prostate cancer with MRI. Extradomain B fibronectin (EDB-FN), an oncoprotein present in aggressive tumors, is a promising molecular target for detection and stratification of high-risk prostate cancer. In this work, we have identified four small peptides (GVK, IGK, SGV, and ZD2) specific to EDB-FN for tumor targeting. In silico simulations of the binding patterns and affinities of peptides to the EDB protein fragment revealed different binding site to different peptide in the ligand-receptor interactions. Tumor specificity and organ distribution of the peptides were assessed using fluorescence imaging in male mice bearing PC-3 human prostate cancer xenografts. Targeted contrast agents were synthesized by conjugating tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the peptides in the solid phase, followed by complexation with GdCl3. The contrast agents were characterized by MALDI-TOF mass spectrometry and relaxivity measurements. All four peptide Gd-DOTA conjugates resulted in robust tumor contrast enhancement in MR imaging of the PC3 mouse prostate cancer model. The peptide Gd-DOTA conjugates specific to EDB-FN are promising targeted small molecular macrocyclic contrast agents for MR molecular imaging of prostate cancer.
AB - Contrast enhanced MRI is commonly used in imaging and treatment planning of prostate cancer. However, no tumor targeting contrast agent is commercially available for accurate detection and characterization of prostate cancer with MRI. Extradomain B fibronectin (EDB-FN), an oncoprotein present in aggressive tumors, is a promising molecular target for detection and stratification of high-risk prostate cancer. In this work, we have identified four small peptides (GVK, IGK, SGV, and ZD2) specific to EDB-FN for tumor targeting. In silico simulations of the binding patterns and affinities of peptides to the EDB protein fragment revealed different binding site to different peptide in the ligand-receptor interactions. Tumor specificity and organ distribution of the peptides were assessed using fluorescence imaging in male mice bearing PC-3 human prostate cancer xenografts. Targeted contrast agents were synthesized by conjugating tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to the peptides in the solid phase, followed by complexation with GdCl3. The contrast agents were characterized by MALDI-TOF mass spectrometry and relaxivity measurements. All four peptide Gd-DOTA conjugates resulted in robust tumor contrast enhancement in MR imaging of the PC3 mouse prostate cancer model. The peptide Gd-DOTA conjugates specific to EDB-FN are promising targeted small molecular macrocyclic contrast agents for MR molecular imaging of prostate cancer.
KW - EDB fibronectin
KW - MRI
KW - peptide
KW - prostate cancer
KW - targeted contrast agent
UR - http://www.scopus.com/inward/record.url?scp=85033365945&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85033365945&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.7b00619
DO - 10.1021/acs.molpharmaceut.7b00619
M3 - Article
C2 - 28976766
AN - SCOPUS:85033365945
VL - 14
SP - 3906
EP - 3915
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 11
ER -