Folate Dendrimers as Tumor Specific Contrast Agents

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Ovarian cancer is the leading killer of women with tumors of gynecological origin, and intracranial ependymomas are the third most common primary brain tumors found in children. The long term goal of this project is to develop a magnetic resonance imaging (MRI) contrast agent specific for ovarian tumors, childhood ependymomas, and choroid plexus tumors thus improving the specificity of both the diagnosis of these tumors and the monitoring of the treatment of these tumors. The specific aim of this project is to develop a high relaxivity dendrimer-Gd(III)-chelate based MRI contrast agent with strong avidity to cells expressing the high affinity folate receptor using low molecular weight targeting agents (folic acid) and actively target it to tumor cells in vivo. We are testing two hypotheses. One is that bifunctional Gd(III) chelates with faster proton exchange rates will have higher relaxivities (better efficiency) than those already achieved with bifunctional chelates of clinically approved agents following conjugation to dendrimers, and the other is that these agents have a high enough molecular efficiency (relaxivity) to enhance T1 weighted images, at 1.5 T, of tumors that express the high affinity folate receptor. The experimental approach consists of attaching a new bifunctional Gd(III) macrocyclic chelate to a new class of dendrimers. This class of dendrimers allows us to control the exact number of targeting and reporter molecules and provides a pure compound. Following the synthesis of this agent we will characterize the magnetic properties, determine the optimum number of targeting molecules, determine the number of Gd(III)- chelate complexes needed to alter the tumor contrast, prove targeting specificity in vivo, and determine the pharmacokinetics and biodistribution. We have two in vivo tumor models consisting of human ovarian tumor xenografts in nude mice that either express the high affinity folate receptor or lack it. The significance of developing a relatively low molecular weight (relative to antibody targeted systems) tumor specific MRI contrast agent is that it will allow better tumor visualization, interpretation for cancer diagnosis, and most significantly a noninvasive method for monitoring tumor therapy.