Background

[PubMed]

Magnetic resonance imaging (MRI) maps information about tissues spatially and functionally. Protons (hydrogen nuclei) are widely used in imaging because of their abundance in water molecules. Water comprises ~80% of most soft tissue. The contrast of proton MRI depends primarily on the density of the nucleus (proton spins), the relaxation times of the nuclear magnetization (T1, longitudinal, and T2, transverse), the magnetic environment of the tissues, and the blood flow to the tissues. However, insufficient contrast between normal and diseased tissues requires the development of contrast agents. Most contrast agents affect the T1 and T2 relaxation times of the surrounding nuclei, mainly the protons of water. T2* is the spin–spin relaxation time composed of variations from molecular interactions and intrinsic magnetic heterogeneities of tissues in the magnetic field (1). Cross-linked iron oxide nanoparticles and other iron oxide formulations affect T2 primarily and lead to decreased signals. On the other hand, paramagnetic T1 agents, such as gadolinium (Gd³⁺) and manganese (Mn²⁺), accelerate T1 relaxation and lead to brighter contrast images.

Extracellular matrix adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (2). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (3). A meshwork of clotted plasma protein was present in the tumor stroma but not in normal tissues, providing a functional matrix for angiogenesis, cell migration, and tumor cell invasion (4). There are high levels of collagens, fibronectin, and fibrin in the tumor connective tissues.

Gadolinium (Gd), a lanthanide metal ion with seven unpaired electrons, has been shown to be very effective in enhancing proton relaxation because of its high magnetic moment and water coordination (5, 6). Gd-labeled diethylenetriaminepentaacetic acid (Gd-DTPA) was the first intravenous MRI contrast agent used clinically, and a number of similar Gd chelates have been developed in an effort to further improve clinical use. However, these low molecular weight Gd chelates have short blood and tissue retention times, which limit their use as imaging agents in the vasculature and cancer. Furthermore, they are largely nonspecific. CGLIIQKNEC (CLT1), a fibronectin-fibrin binding peptide, was identified with phage display screening (4). The peptide was conjugated with Gd-DTPA to form Gd-DTPA-CLT1 for imaging of fibronectin-fibrin complexes in tumor tissues (7).

Synthesis

[PubMed]

DTPA-CLT1 was synthesized with solid-phase synthesis (7). DTPA was conjugated to the N-terminal of CLT1 peptide. Gd(OAc)₃ and DTPA-CLT1 were incubated at pH 6. The product, Gd-DTPA-CLT1 (1:1:1), was isolated with high-performance liquid chromatography. The mass (m/z, M + H⁺) of Gd-DTPA-CLT1 was 1,650.75 as determined with mass spectrometry (calculated: 1,650.20).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Gd-DTPA-CLT1 exhibited T1 and T2 relaxivity values of 4.22 mM^-1 and 4.45 mM^-1 at 3T, respectively (7).

Animal Studies

Human Studies

[PubMed]

No publication is currently available.

NIH Support

R01 CA097465

References

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Pilch J., Brown D.M., Komatsu M., Jarvinen T.A., Yang M., Peters D., Hoffman R.M., Ruoslahti E. Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds. Proc Natl Acad Sci U S A. 2006;103(8):2800–4. [PMC free article: PMC1413849] [PubMed: 16476999]

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Brasch R.C. New directions in the development of MR imaging contrast media. Radiology. 1992;183(1):1–11. [PubMed: 1549653]

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Runge V.M., Gelblum D.Y. Future directions in magnetic resonance contrast media. Top Magn Reson Imaging. 1991;3(2):85–97. [PubMed: 2025435]

7.

Ye F., Wu X., Jeong E.K., Jia Z., Yang T., Parker D., Lu Z.R. A peptide targeted contrast agent specific to fibrin-fibronectin complexes for cancer molecular imaging with MRI. Bioconjug Chem. 2008;19(12):2300–3. [PMC free article: PMC2651601] [PubMed: 19053180]