The objectives of this research project are to synthesize and develop novel targeted nanoglobular gadolinium(III) chelates as safe, effective and tumor-specific contrast agents for diagnostic cancer imaging with magnetic resonance imaging (MRI). The FDA approved clinical MRI contrast agents are nonspecific agents. High doses are often used to achieve accurate cancer diagnosis. However, it has been recently reported that high doses of gadolinium-based contrast agents can cause potentially fatal nephrogenic systemic fibrosis in some patients with renal malfunctions. We believe that an effective tumor specific contrast agent can substantially reduce the injected dose for accurate cancer detection and, therefore, greatly minimize the toxic side effects of gadolinium- based contrast agents. We propose to design, synthesize and evaluate tumor-specific peptide targeted nanoglobular Gd-DO3A conjugates as novel targeted MRI contrast agents for diagnostic cancer imaging. The targeted contrast agents will result in effective tumor specific contrast enhancement at a substantially reduced dose and rapidly eliminate from the body after the MRI examinations. They will significantly improve the safety index of contrast enhanced MRI in cancer diagnosis.
The specific aims of the projects are to design, synthesize and characterize tumor-specific peptide targeted nanoglobular Gd-DO3A conjugates from compact and three-dimensional symmetric nanoglobular macromolecules as targeted MRI contrast agents; to evaluate the physicochemical properties, including transmetallation stability and relativity, and biological properties, including cytotoxicity, hemotoxicity and tumor binding of the targeted nanoglobular MRI contrast agents; to investigate the efficacy of the targeted nanoglobular contrast agents for tumor-specific contrast enhanced MR imaging in animal tumor models at reduced doses; to evaluate in vivo toxicological and pharmaceutical properties, including acute and subacute toxicity, pharmacokinetics, elimination, Gd tissue accumulation and tumor targeting of the targeted nanoglobular MRI contrast agents. The long-term goal is to develop safe, effective and targeted MRI contrast agents for specific cancer imaging.
Novel tumor-specific MRI contrast agents will be designed and developed for more accurate and earlier cancer detection. Accurate cancer diagnosis will be achieved with the targeted contrast agents at a substantially reduced dose, which will further improve the safety of contrast enhanced MRI.
|Tan, Mingqian; Ye, Zhen; Lindner, Daniel et al. (2014) Synthesis and evaluation of a targeted nanoglobular dual-modal imaging agent for MR imaging and image-guided surgery of prostate cancer. Pharm Res 31:1469-76|
|Chow, April M; Tan, Mingqian; Gao, Darwin S et al. (2013) Molecular MRI of liver fibrosis by a peptide-targeted contrast agent in an experimental mouse model. Invest Radiol 48:46-54|
|Wu, Xueming; Lindner, Daniel; Yu, Guan-Ping et al. (2013) MR molecular imaging of prostate cancer with a small molecular CLT1 peptide targeted contrast agent. J Vis Exp :|
|Zhou, Zhuxian; Wu, Xueming; Kresak, Adam et al. (2013) Peptide targeted tripod macrocyclic Gd(III) chelates for cancer molecular MRI. Biomaterials 34:7683-93|
|Zhou, Zhuxian; Lu, Zheng-Rong (2013) Gadolinium-based contrast agents for magnetic resonance cancer imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol 5:1-18|
|Tan, Mingqian; Burden-Gulley, Susan M; Li, Wen et al. (2012) MR molecular imaging of prostate cancer with a peptide-targeted contrast agent in a mouse orthotopic prostate cancer model. Pharm Res 29:953-60|
|Wu, Xueming; Burden-Gulley, Susan M; Yu, Guan-Ping et al. (2012) Synthesis and evaluation of a peptide targeted small molecular Gd-DOTA monoamide conjugate for MR molecular imaging of prostate cancer. Bioconjug Chem 23:1548-56|
|Ye, Furong; Jeong, Eun-Kee; Parker, Denis et al. (2011) Evaluation of CLT1-(Gd-DTPA) for Cancer MR Molecular Imaging in a Mouse Breast Cancer Model. Bo Pu Xue Za Zhi 2:325-330|
|Tan, Mingqian; Ye, Zhen; Jeong, Eun-Kee et al. (2011) Synthesis and evaluation of nanoglobular macrocyclic Mn(II) chelate conjugates as non-gadolinium(III) MRI contrast agents. Bioconjug Chem 22:931-7|
|Tan, Mingqian; Lu, Zheng-Rong (2011) Integrin Targeted MR Imaging. Theranostics 1:83-101|
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