Peptide targeted tripod macrocyclic Gd(III) chelates for cancer molecular MRI.

Abstract

Rational design and develop of targeted contrast agents binding to cancer-related proteins will achieve more accurate cancer diagnosis and prognosis by magnetic resonance (MR) imaging. CREKA is a tumor-homing pentapeptide (Cys-Arg-Glu-Lys-Ala) specifically homes to fibrin-fibronectin complexes abundantly expressed in tumor microenvironment. In this study, we developed and evaluated a CREKA peptide targeted multiplexed Gd-MR probe (CREKA-Tris-Gd(DOTA)3) for MR imaging of breast tumors. CREKA and azide bearing Gd(III) was attached to a maleimide-functional trialkyne scaffold via thiol-maleimide and azide-alkyne click chemistry, respectively. CREKA-Tris-Gd(DOTA)3 has a well-defined structure with a molecular weight of 2914 Da. The T1 relaxivity of CREKA-Tris-Gd(DOTA)3 is 8.06 mM(-1) s(-1) per Gd (24.18 mM(-1) s(-1) per molecule) at room temperature and 3 T. Fluorescence imaging showed high binding specificity of CREKA to a 4T1 breast tumor model in mice while it was not found for the scrambled CREKA (CERAK). The CREKA peptide-targeted contrast agent resulted in greater contrast enhancement than the corresponding CERAK agent and the commercialized contrast agent ProHance(®) in tumor at a dose of 0.1 mmol Gd/kg in female athymic mice bearing 4T1 breast carcinoma xenograft. This small molecular contrast agent was easily excreted from body after imaging indicated low toxicity. The targeted MRI contrast agent has a potential for specific cancer molecular imaging with MRI.

• Authors: Zhuxian Zhou, Xueming Wu, Adam Kresak, Mark Griswold, Zheng-Rong Lu
• Journal: Biomaterials (Biomaterials) Vol. 34 Issue 31 Pg. 7683-93 (Oct 2013) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 23863450 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2013. Published by Elsevier Ltd.

Chemical References

• CREKA-Tris(Gd-DOTA)3
• Contrast Media
• Coordination Complexes
• Oligopeptides
• Gadolinium

Topics

• Animals
• Breast Neoplasms (diagnosis)
• Contrast Media (chemistry)
• Coordination Complexes (chemistry)
• Female
• Fluorescent Antibody Technique
• Gadolinium (chemistry)
• Magnetic Resonance Imaging (methods)
• Mice
• Mice, Inbred BALB C
• Oligopeptides (chemistry)