Folate Dendrimers as Tumor Specific Contrast Agents

卵巢癌是女性妇科肿瘤的主要杀手，颅内室管膜瘤是儿童中第三大常见的原发性脑肿瘤。该项目的长期目标是开发一种针对卵巢肿瘤、儿童室管膜瘤和脉络膜丛肿瘤的磁共振成像（MRI）造影剂，从而提高这些肿瘤的诊断和治疗监测的特异性。本项目的具体目标是利用低分子量靶向剂（叶酸）开发一种高弛豫树突状- gd （III）螯合物为基础的MRI造影剂，对表达高亲和力叶酸受体的细胞有很强的亲和力，并在体内主动靶向肿瘤细胞。我们正在测试两个假设。一是质子交换速率更快的双功能Gd（III）螯合物将比临床批准的双功能螯合物在与树状大分子结合后具有更高的弛缓性（更好的效率），另一个是这些药物具有足够高的分子效率（弛缓性），可以增强表达高亲和力叶酸受体的肿瘤在1.5 T时的T1加权图像。实验方法包括将一个新的双功能Gd（III）大环螯合物连接到一类新的树状大分子上。这类树状大分子使我们能够控制靶向和报告分子的确切数量，并提供一种纯化合物。随着该药物的合成，我们将表征其磁性，确定最佳靶向分子数量，确定改变肿瘤对比所需的Gd(III)-螯合物的数量，证明其体内靶向特异性，并确定其药代动力学和生物分布。我们在裸鼠体内建立了两种由人卵巢肿瘤异种移植物组成的肿瘤模型，它们要么表达高亲和力叶酸受体，要么缺乏叶酸受体。开发相对低分子量（相对于抗体靶向系统）的肿瘤特异性MRI造影剂的意义在于，它将允许更好的肿瘤可视化，对癌症诊断的解释，最重要的是，它是一种监测肿瘤治疗的无创方法。

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.