Metal Chelate Conjugated Dendrimer Constructs for Diagno

用于诊断的金属螯合物共轭树枝状聚合物构建体

• 批准号: 6947705
• 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/6947705
• 关键词: angiography; bioimaging /biomedical imaging; breast neoplasms; chelating agents; chemical conjugate; contrast media; diagnosis design /evaluation; gadolinium; immunoconjugates; kidney imaging /visualization; liver neoplasms; lymphatic system; magnetic resonance imaging; molecular size; neoplasm /cancer blood supply; neoplasm /cancer diagnosis; neoplasm /cancer radionuclide therapy; neutron radiation

Macromolecular agents composed of serum albumin or linear polymers have MRI contrast enhancement factors less than those predicted for rigid molecules of comparable size. MRI contrast agents based upon dendrimers obviate this deficiency. Terminal primary amines of dendrimers modified with appropriate chelating agents that effectively complex Gd(III) complexes are developed in our laboratories. These reagents possess a molar relaxivity of up to 6 times that of Gd(III)DTPA. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained. Studies continue to thoroughly explore the utility of these agents. These macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents can be tuned for various applications by adjusting tuning several fundamental criteria: generation (MW & size), core elements (lipophilicity & charge), PEG conjugation, lysine co-administration (renal clearance), and conjugation to targetng vectors (molecular targeting). PAMAM based agents have imaged murine tumor vasculature accurately at the 200 micron scale. DAB based agents have selective properties wherein reverse contrast images of 0.3 mm metastatic liver tumors are detected. These agents can be selectively targeted, not only by conjugation to antibodies, but by other vectors to deliver exceptionally high levels of Gd(III) into disseminated intraperitoneal ovarian cancer tumor. Recent results include: (1) assessment of chemotherapy induced renal toxicity whereby the MRI images of damaged kidney correlate with standard blood chemistries; (2) imaging of the lymphatic system with particular attention to involvement of the lymph nodes relating to lymphoma; (3) imaging of breast cancer involvement with drainage to sentinal nodes for lymph node involvement diagnosis; and (4) effects of external beam radiation on then integrity of tumor vasculature.

由血清白蛋白或线性聚合物组成的大分子药物的 MRI 对比度增强因子小于对相当大小的刚性分子的预测值。基于树枝状聚合物的 MRI 造影剂消除了这一缺陷。我们的实验室开发了用适当的螯合剂修饰的树枝状聚合物的末端伯胺，可以有效地络合 Gd(III) 络合物。这些试剂的摩尔弛豫率高达 Gd(III)DTPA 的 6 倍。获得了出色的常规全身 MR 成像和 3D T-O-F MR 血管造影。研究仍在继续深入探索这些药物的效用。这些基于大分子螯合物缀合的树枝状大分子的 Gd(III) MR 造影剂可以通过调整几个基本标准来调整以适应各种应用：生成（分子量和大小）、核心元素（亲脂性和电荷）、PEG 缀合、赖氨酸共同给药（肾）清除），以及与 targetng 载体缀合（分子靶向）。基于 PAMAM 的试剂已在 200 微米尺度上对小鼠肿瘤脉管系统进行了精确成像。基于 DAB 的试剂具有选择性特性，其中可检测 0.3 毫米转移性肝肿瘤的反向对比图像。这些药物不仅可以通过与抗体结合，还可以通过其他载体选择性靶向，将极高水平的 Gd(III) 递送至播散性腹膜内卵巢癌肿瘤中。最近的结果包括：（1）评估化疗引起的肾毒性，其中受损肾脏的 MRI 图像与标准血液化学成分相关； (2) 淋巴系统成像，特别注意与淋巴瘤相关的淋巴结受累； (3)乳腺癌受累影像学检查并引流至前哨淋巴结以诊断淋巴结受累； (4)外部束辐射对肿瘤脉管系统完整性的影响。