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可比大小的刚性分子的预测值。基于树枝状聚合物的MRI造影剂弥补了这一缺陷。在我们的实验室中开发了用适当的螯合剂修饰的树枝状聚合物的末端伯胺，其有效地络合Gd（III）络合物。这些试剂具有高达Gd（III）DTPA的6倍的摩尔弛豫率。获得了良好的常规全身MR成像和3D T-O-F MR血管造影。研究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聚合物的Gd（III）MR造影剂可以通过调整调谐几个基本标准来针对各种应用进行调谐：生成（MW和大小）、核心元件（亲脂性和电荷）、PEG缀合、赖氨酸共施用（肾清除率）和与靶向载体的缀合（分子靶向）。基于PAMAM的试剂在200微米尺度下准确地成像了鼠肿瘤血管系统。基于DAB的试剂具有选择性性质，其中检测到0.3mm转移性肝肿瘤的反向对比度图像。这些药物可以选择性地靶向，不仅通过与抗体缀合，而且通过其他载体将异常高水平的Gd（III）递送到播散性腹膜内卵巢癌肿瘤中。最近的成果包括：（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）乳腺癌受累的成像，引流至前哨淋巴结，用于淋巴结受累诊断;（4）外照射对肿瘤血管完整性的影响。