Metal Chelate Conjugated Dendrimer Constructs for Diagno

由血清白蛋白或线状聚合物组成的大分子药物，其MRI对比增强因子比同等大小的刚性分子预测的要小。基于树突分子的MRI造影剂消除了这一缺陷。用适当的螯合剂修饰树状大分子的末端伯胺，有效地配合Gd（III）配合物，在我们的实验室开发。这些试剂的摩尔弛豫率高达Gd(III)DTPA的6倍。获得了良好的常规全身磁共振成像和3D T-O-F磁共振血管成像。研究继续深入探索这些药物的效用。这些大分子螯合共轭树突状分子Gd(III) MR造影剂可以通过调整几个基本标准来调整各种应用：生成（分子量和大小）、核心元素（亲脂性和电荷）、PEG偶联、赖氨酸共给药（肾脏清除）和偶联到靶向载体（分子靶向）。基于PAMAM的药物可以在200微米尺度上精确成像小鼠肿瘤血管系统。基于DAB的试剂具有选择性，其中0.3 mm转移性肝肿瘤的反向对比图像被检测到。这些药物不仅可以与抗体结合，还可以通过其他载体选择性靶向，将异常高水平的Gd（III）输送到弥散性腹腔内卵巢癌肿瘤中。最近的研究结果包括：(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相关；(2)淋巴系统影像学检查，特别注意与淋巴瘤有关的淋巴结受累情况；(3)乳腺癌累及前哨淋巴结引流的影像学诊断；(4)外束辐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.