METAL CHELATE CONJUGATED DENDRIMER CONSTRUCTS FOR DIAGNOSIS & THERAPY

由血清白蛋白或线性聚合物组成的大分子制剂 MRI对比度增强系数是否低于刚性预测 大小相当的分子。这归功于灵活性和 聚合物链中的链段运动。为了消除这一缺陷， 一种新型的核磁共振造影剂是基于 聚酰胺胺形式的星爆型树枝状大分子，其中端胺 用络合剂修饰后，再用Gd络合物 形成了。这种结构已经被证明具有摩尔松弛向上 到目前临床使用的简单Gd-DTPA的6倍， 而且比其他大分子试剂的两倍还要好。正如我们所做的那样 能够展示出色的常规磁共振成像和3D时间 飞行磁共振血管造影术，研究已经扩大到彻底探索 这些试剂的用途，并确定树枝状大小的影响 (清除和定位)，包括Gd络合物的数量 在结构内(弛豫度和电荷的影响)，和毒性 这类特工。在啮齿动物身上进行了初步的工作 模型，上述研究计划在犬模型系统中进行。 此外，已经为这次调查获得了CRADA，以确保 树枝状大分子的供应以及保持其一致性和 纯洁。 初步实验证明，螯合铋(III)与 树枝状大分子用作CT时，在摩尔基础上具有更强的对比度 造影剂与目前使用的碘基造影剂相比 诊所。为了进一步研究树枝状大分子的这种用途，研究已经 已经开始比较基于碘白蛋白的CT试剂的使用与 碘-树枝状分子CT造影剂与螯合铋(III)-树枝状分子的比较 以造影剂为基础。

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. This is attributed to the flexibility and segmental motions within the polymer chain. To obviate this deficiency, a new class of MRI contrast agents has been developed based upon the polyamidoamine form of Starburst dendrimers wherein the terminal amines are modified with chelating agents and then gadolinium complexes are formed. Such constructs have been shown to possess a molar relaxivity up to 6 times that of the simple Gd-DTPA currently employed in the clinic, and better than twice that of other macromolecular agents. As we have been able to demonstrate excellent conventional MR imaging and 3D time of flight MR angiograms, 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 of this class of agent. A preliminary work has been performed in rodent models, the above studies are planned to proceed in canine model systems. Additionally, a CRADA has been secured for this investigation to assure a supply of the dendrimers as well as to maintain their consistency and purity. Preliminary experiments have demonstrated the chelated Bi(III) bound to dendrimers possessed greater contrast on a molar basis when employed as CT contrast agents when compared to the iodine based agents currently used in the clinic. To further investigate this use of dendrimers, studies have been initiated to compare the use of iodine-albumin based CT agents versus iodine-dendrimer CT contrast agents versus Chelated Bi(III)-dendrimer based contrast agents.