Folate Dendrimers as Tumor Specific Contrast Agents

卵巢癌是妇科肿瘤的主要杀手，而颅内室管膜瘤是儿童中第三常见的原发性脑肿瘤。该项目的长期目标是开发一种特异性用于卵巢肿瘤、儿童室管膜瘤和脉络丛肿瘤的磁共振成像（MRI）造影剂，从而提高这些肿瘤诊断和这些肿瘤治疗监测的特异性。 该项目的具体目的是开发一种高弛豫率树枝状聚合物-Gd（III）-螯合物基MRI造影剂，其对表达高亲和力叶酸受体的细胞具有强亲合力，使用低分子量靶向剂（叶酸）并将其主动靶向体内肿瘤细胞。 我们正在测试两个假设。 一个是具有更快质子交换速率的双功能Gd（III）螯合物将具有比在与树枝状聚合物缀合后用临床批准的试剂的双功能螯合物已经实现的那些更高的弛豫率（更好的效率），另一个是这些试剂具有足够高的分子效率（弛豫率）以增强表达高亲和力叶酸受体的肿瘤在1.5T下的T1加权图像。 实验方法包括附加一个新的双功能Gd（III）大环螯合物的一类新的树枝状聚合物。 这类树枝状聚合物允许我们控制靶向和报告分子的确切数量，并提供纯化合物。 在合成该药剂之后，我们将表征磁性，确定靶向分子的最佳数量，确定改变肿瘤对比度所需的Gd（III）螯合物的数量，证明体内靶向特异性，并确定药代动力学和生物分布。 我们有两个体内肿瘤模型，包括人卵巢肿瘤裸鼠移植瘤，表达高亲和力叶酸受体或缺乏it. Significance的发展相对低分子量（相对于抗体靶向系统）的肿瘤特异性MRI造影剂是，它将允许更好的肿瘤可视化，解释癌症诊断，最重要的是一个非侵入性的方法，用于监测肿瘤治疗。

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.