METAL CHELATE CONJUGATED DENDRIMER CONSTRUCTS FOR DIAGNOSIS & THERAPY

用于诊断的金属螯合物共轭树枝状大分子结构

• 批准号: 6123736
• 负责人: MARTIN W BRECHBIEL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6123736
• 关键词: Rodentias; albumins; bismuth; chelating agents; chemical conjugate; computed axial tomography; contrast media; cytotoxicity; diagnosis design /evaluation; dogs; iodine; macromolecule; magnetic resonance imaging; neoplasm /cancer diagnosis; neoplasm /cancer therapy; polymers

"Macromolecular agents composed of either serum albumins or linear polymers have MRI contrast enhancement factors less than those predicted for rigid molecules of comparable size, attributed to the flexibility and segmental motions within the polymer chain. To obviate this deficiency, MRI contrast agents have been developed based upon Starburst PAMAM dendrimers, wherein terminal primary amines are modified with chelating agents and then gadolinium complexes formed. Such constructs possess a molar relaxivity up to 6 times that of simple Gd-DTPA, currently employed in the clinic, and better than twice that of other macromolecular agents. Excellent conventional MR imaging and 3D time of flight MR angiograms have been obtained and studies have been expanded to thoroughly explore the utility of these agents and to determine the effects of dendrimer size (clearance and localization), the number of gadolinium complexes included within the construct (relaxivity and effects of charge), and toxicity. Ongoing experiments in a canine model system have already demonstrated outstanding detailed imaging of the vasculature and potential development as blood pool agents when using the G6 generation dendrimer construct. Due to results indicative of vasculature leakage of this particular reagent, this study has been modified and the G8 dendrimer is currently being evaluated for utility as an MRI contrast agent. A CT contrast agent based upon albumin conjugated to iopanoic is vcurrnetly being evaluated in pre-clinical models for use in quantitating flow and dispersion of therapeutics being injected inter-cranially. This material is being compared versus a comparable MRI albumin based reagent and preparations are underway to prepare the iodine based reagent for use in clinical trials. Use of dendrimers to augment the number of chelates conjugated to monoclonal antibodies, and then greatly increase both specific activity for therapeutic applications and radiolabeling efficiency, was examined. Exceptionally good non- specific targeting of radio-sensitive organs was promoted by the dendrimer itself and although this could be partially controlled by manipulation of charge through metal complex formation, this technology was deemed counter-productive and discontinued for this specific application."

“由任一血清组成的大分子制剂 白蛋白或线性聚合物具有MRI对比度增强作用 因素少于对可比较的刚性分子的预测 尺寸，归因于内部的灵活性和分段运动 聚合物链。为了消除这种缺陷，MRI 造影剂 是基于 Starburst PAMAM dendrimers 开发的， 其中末端伯胺用螯合剂修饰 然后形成钆络合物。此类构建体具有 目前，摩尔弛豫率高达简单 Gd-DTPA 的 6 倍 在诊所工作，比其他人好两倍 高分子制剂。出色的传统 MR 成像和 已获得 3D 飞行时间 MR 血管造影照片并进行研究 已扩展以彻底探索这些的效用 剂并确定树枝状聚合物尺寸的影响（间隙和 定位），其中包含的钆配合物的数量 结构（弛豫性和电荷效应）和毒性。 正在进行的犬模型系统实验已经 表现出出色的脉管系统详细成像 使用 G6 时作为血池剂的潜在发展 一代树枝状聚合物构建体。由于结果表明 这种特殊试剂的脉管系统泄漏，这项研究已经 修改后，G8 树枝状大分子目前正在评估 作为 MRI 造影剂的用途。一种 CT 造影剂 目前正在评估与碘泛酸结合的白蛋白 用于定量流动和分散的临床前模型 颅内注射治疗药物。该材料正在 与基于 MRI 白蛋白的类似试剂进行比较 正在准备制备碘基试剂 用于临床试验。使用树枝状聚合物来增加 螯合物与单克隆抗体缀合，然后极大地 增加治疗应用的比活性和 放射性标记效率进行了检查。非常好的非 促进以放射敏感器官为具体目标 树枝状聚合物本身，尽管这可以部分控制 通过形成金属络合物来操纵电荷，这 该技术被认为会适得其反，并已停止使用 这个特定的应用程序。”