Design of targeted MRI contrast agents for early cancer detection

摘要

Introduction: Molecular imaging of high-risk cancer with metastatic potential has a potential to detect the life threatening disease earlier, to guide better treatment design, and to timely monitor therapeutic response. We have designed and tested small molecular targeted Gd(Ⅲ) based MRI contrast agents to target fibronectin, a hallmark of EMT, highly expressed in the ECM of aggressive tumors for early detection and differential diagnosis of high-risk cancer, including breast cancer and prostate cancer. Materials and Methods: Targeted MRI contrast agents are synthesized by the conjugation of small peptides specific to the biomarkers to macrocyclic Gd(Ⅲ) chelates Gd-DOTA or Gd(HP-DO3A). The expression of the biomarkers in tumor was determined by western blot. The binding of the peptides was determined by fluorescence imaging. The effectiveness of the targeted MRI contrast agents for cancer molecular imaging has been tested in mice bearing prostate cancer or metastatic breast cancer on a Bruker 7T animal MRI scanner. The ability of the targeted MRI contrast agents in detecting microscopic tumors was validated by cryo-imaging. Results: Fibronectin, especially oncofetal fibronectin, is highly expressed in high-risk tumors. The peptides specifically bound to the molecular targets in tumor ECM. The targeted contrast agents produced strong tumor enhancement for effective tumor detection with MRI. MRI with the targeted contrast agents was able to detect breast cancer micrometastases with a size as small as 300 microns, which is validated by fluorescence cryo-imaging. The targeted contrast agents are also able to monitor the growth of detected metastases with MRI. Conclusion: Small molecular peptide targeted MRI contrast agents specific to fibronectin and oncofetal fibronectin are effective to produce strong contrast enhancement in cancer and micrometastases for early cancer detection with MRI. They have the potential for clinical translation in detection and clinical management of high-risk cancer.