Metal Chelate Conjugated Dendrimer Constructs for Diagno

由血清白蛋白或线性聚合物组成的大分子试剂的MRI对比度增强因子比同等大小的刚性分子预测的要小。基于树枝状大分子的MRI造影剂消除了这一缺陷。我们实验室开发了用适当的螯合剂修饰的树枝状大分子的末端伯胺，从而有效地络合了Gd(III)配合物。这些试剂的摩尔松弛系数高达Gd(III)DTPA的6倍。获得了良好的常规全身MR成像和3D T-O-F磁共振血管成像。研究继续深入探索这些制剂的效用。这些基于大分子螯合共轭树枝状大分子的Gd(III)MR造影剂可以通过调整几个基本标准来调整，以适应不同的应用：生成(分子量和大小)、核心元素(亲脂性和电荷)、聚乙二醇偶联物、赖氨酸共给药(肾脏清除)和与靶向载体的偶联性(分子靶向)。以PAMAM为基础的试剂已经在200微米范围内准确地成像了小鼠肿瘤血管。基于DAB的试剂具有选择性，其中可以检测0.3 mm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的偶联，而且可以通过其他载体选择性地靶向，以将异常高水平的Gd(III)输送到播散性的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，即受损肾脏的MRI图像与标准血液化学指标相关联；(2)淋巴系统成像，特别注意与淋巴瘤相关的淋巴结受累；(3)乳腺癌累及前哨淋巴结的成像，用于淋巴受累的诊断；(4)外照射对肿瘤血管完整性的影响。

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.