BERKELEY, CA (UroToday.com) - Prostate cancer is one of the leading causes of the deaths of males in the United States. Early detection and diagnosis of malignant prostate tumors is critical for formulating appropriate treatment to achieve the best therapeutic outcomes. Molecular imaging of cancer-related biomarkers allows non-invasive detection and characterization of prostate tumors and assessment of therapeutic efficacy. Various imaging modalities have been applied for detecting, characterizing, staging, and follow-up of prostate cancer. Ultrasound imaging is the commonly used modality for evaluating the prostate and for guiding needle biopsies but has a limited use in the detection and characterization of prostate cancer. Although CT is widely used in patients with newly diagnosed prostate cancer, it is not effective for cancer molecular imaging. Positron emission tomography (PET) is highly sensitive for molecular imaging and can measure tumor glucose metabolic rate using [18F]-fluoro-2-deoxy-D-glucose (FDG).[1, 3, 4] Recent development of PET/CT and PET/MRI dual imaging modalities enables co-registration of PET molecular imaging with CT or MRI anatomic imaging to improve both imaging sensitivity and specificity.
Magnetic resonance imaging (MRI) provides high-resolution images of the anatomic structure of soft tissues. Contrast-enhanced MRI alone has a potential for detecting and characterizing prostate cancer based on the molecular signatures of prostate cancer with high spatial resolution. However, clinical application of contrast-enhanced MRI for cancer molecular imaging is limited by the relatively low sensitivity of MRI, low concentration of these biomarkers on the surface of cancer cells, and lack of safe and effective contrast agents. The limitations can be overcome by selecting proper molecular biomarkers abundantly present in diseased tissues and with little presence in normal tissues. The targeted Gd(III)-based contrast agents should also be readily excreted from the body after diagnostic imaging to minimize potential toxic side effects. Targeted stable Gd(III) chelates, with sizes smaller than renal filtration threshold, are the promising targeted MRI contrast agents for clinical cancer molecular imaging.
In the present study, a small peptide targeted Gd(III) chelate was designed for MR-molecular imaging of a cancer-related biomarker, clotted plasma proteins, which abundantly exist in tumor stroma and rarely in normal tissues in prostate cancer. The targeted contrast agent CLT1-dL-(Gd-DOTA)4 contains a CLT1 peptide as the targeting moiety, which showed strong binding to the PC3 prostate tumor model, and four highly stable Gd(III) DOTA monoamide chelates. The effectiveness of CLT1-dL-(Gd-DOTA)4 for MR molecular imaging of the prostate tumor was determined in an orthotopic xenograft PC3 prostate tumor model in male athymic nude mice. The agent produced significant contrast enhancement in the prostate tumor at a relatively low dose. The agent has shown a great potential for the detection of small malignant prostate tumors with contrast-enhanced MRI.
There are several limitations to in this study. First, CLT1 may not be stable against proteolytic degradation, which may lead to rapid washout of the agent from the target site. Modification of CLT1 with D-amino acids may improve the stability of the peptide and prolong the binding of the agent at the target. Second, it is still not clear about exact components in the clotted plasma proteins that the CLT1 peptide binds to. The clotted plasma proteins contain many proteins such as fibrin and fibronectin. The exact binding site needs to be clarified in the future work.
Despite of these limitations, the study has demonstrated that it is feasible for effective MR molecular imaging of cancer biomarkers abundantly expressed in tumor stroma of prostate cancer with a small molecular peptide targeted MRI contrast agent. The targeted contrast agent is promising to be further developed for detection and characterization of prostate cancer. New targeted-contrast agents can also be designed for molecular imaging of other unique cancer-related extracellular matrix proteins in prostate cancer. Many of the proteins are associated with tumor angiogenesis and malignancy of prostate cancer. Contrast-enhanced MRI with the targeted contrast agents specific to these biomarkers has a potential for detecting, characterizing, staging, and follow-up of prostate cancer based on their expression.
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- Wu, X.; Burden-Gulley, S. M.; Yu, G. P.; Tan, M.; Lindner, D.; Brady-Kalnay, S. M.; Lu, Z. R. Synthesis and Evaluation of a Peptide Targeted Small Molecular Gd-DOTA Monoamide Conjugate for MR Molecular Imaging of Prostate Cancer. Bioconjugate Chem. 2012, 23, 1548-1556.
Xueming Wu,1 Susan M. Burden-Gulley,2 Guan-Ping Yu,1 Mingqian Tan,1 Daniel Lindner,3 Susann M. Brady-Kalnay,2 and Zheng-Rong Lu1,† as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
1Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA
2Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
3Dept. of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, Ohio 44195, USA