METAL CHELATE CONJUGATED DENDRIMER CONSTRUCTS FOR DIAGNOSIS & THERAPY

“高分子制剂由血清 白蛋白或线性聚合物具有MRI对比增强 系数小于那些预测的刚性分子的可比 大小，归因于内的灵活性和节段性运动 聚合物链为了弥补这一缺陷，MRI造影剂 已经基于Starburst PAMAM树枝状聚合物开发， 其中末端伯胺用螯合剂改性 然后形成钆络合物。这种结构具有 摩尔弛豫高达6倍的简单Gd-DTPA，目前 在诊所工作，比其他人好两倍。 大分子药剂出色的常规MR成像， 已经获得了3D飞行时间MR血管造影，并进行了研究 已经扩展到彻底探索这些工具的实用性， 试剂，并确定树枝状聚合物大小的影响（清除率和 局部化），包括在其中的钆络合物的数量 结构（弛豫率和电荷效应）和毒性。 正在进行的犬类模型系统实验已经 显示了出色的血管详细成像， 当使用G6时，作为血池剂的潜在开发 代树枝状聚合物构建体。由于结果表明， 血管泄漏的这种特殊的试剂，这项研究已经 修改和G8树枝状聚合物目前正在评估 用作MRI造影剂。一种CT造影剂， 目前正在评估与碘番酸结合的白蛋白， 用于定量血流和弥散的临床前模型 颅内注射治疗剂。这种材料被 与相当的MRI白蛋白基试剂进行比较， 目前正在准备碘基试剂， 用于临床试验。使用树枝状聚合物来增加 螯合物与单克隆抗体结合， 增加治疗应用的比活性， 放射性标记效率。非常好的非- 放射敏感器官的特异性靶向得到促进， 树枝状聚合物本身，尽管这可以部分地由 通过金属络合物形成来操纵电荷，这 技术被认为是反生产力和停止， 这个具体的应用。"

"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, attributed to the flexibility and segmental motions within the polymer chain. To obviate this deficiency, MRI contrast agents have been developed based upon Starburst PAMAM dendrimers, wherein terminal primary amines are modified with chelating agents and then gadolinium complexes formed. Such constructs possess a molar relaxivity up to 6 times that of simple Gd-DTPA, currently employed in the clinic, and better than twice that of other macromolecular agents. Excellent conventional MR imaging and 3D time of flight MR angiograms have been obtained and 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. Ongoing experiments in a canine model system have already demonstrated outstanding detailed imaging of the vasculature and potential development as blood pool agents when using the G6 generation dendrimer construct. Due to results indicative of vasculature leakage of this particular reagent, this study has been modified and the G8 dendrimer is currently being evaluated for utility as an MRI contrast agent. A CT contrast agent based upon albumin conjugated to iopanoic is vcurrnetly being evaluated in pre-clinical models for use in quantitating flow and dispersion of therapeutics being injected inter-cranially. This material is being compared versus a comparable MRI albumin based reagent and preparations are underway to prepare the iodine based reagent for use in clinical trials. Use of dendrimers to augment the number of chelates conjugated to monoclonal antibodies, and then greatly increase both specific activity for therapeutic applications and radiolabeling efficiency, was examined. Exceptionally good non- specific targeting of radio-sensitive organs was promoted by the dendrimer itself and although this could be partially controlled by manipulation of charge through metal complex formation, this technology was deemed counter-productive and discontinued for this specific application."