The objectives of this research are to develop safe, effective targeted polymer-gadolinium chelate conjugates as contrast agents for magnetic resonance diagnostic cancer imaging. Cancer is one of the leading causes of human death in the United States. The accurate diagnosis and subsequent optimal treatment of cancer at its earliest stage is crucial to save the lives of cancer patients. Magnetic resonance imaging (MRI) is a non-invasive clinical diagnostic technique, but lacks of functional contrast agents for earlier tumor detection and characterization. The novel targeted polymeric contrast agents will increase the sensitivity and accuracy of the detection of small cancers and precancerous tissues with MRI.
The specific aims are to design, synthesize and characterize poly(L-glutamic acid)-gadolinium (111) chelate conjugates and monoclonal antibody Fab' fragment targeted poly(L-glutamic acid)-Gd(lll) chelate conjugates as MRI contrast agents with minimal long-term Gd(lll) tissue accumulation; to evaluate the physicochemical and biological properties, including molecular weight distribution, relaxivity, Gd chelate release, in vivo clearance, biodistribution, neoplastic targeting, pharmacokinetics and safety, of the targeted and nontargeted conjugates; to assess the efficacy of the targeted and nontargeted conjugates on tumor contrast enhancement in MR imaging. The biocompatible poly(L-glutamic acid) will be used as a carrier and Gd(III)DOTA will be conjugated to the polymer via cleavable spacers, which will be readily cleaved to release the Gd chelate from the polymer and to facilitate its clearance from the body after the MRI exam. Monoclonal antibody Fab' fragments against the molecular markers expressed in neoplastic tissues will be incorporated into the polymer conjugates to achieve tumor specific contrast enhancement in MRI. The targeted contrast agents will be able to bind to the molecular targets and deliver a sufficient amount of paramagnetic chelates in target tissues for the imaging of small cancers. The structural, physicochemical and biological properties of the conjugates will be further optimized to develop safe, efficacious contrast agents for more accurate cancer detection and staging with MRI. The long-term goal of this project is to develop safe, effective, functional contrast agents for clinical MR cancer imaging.
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