Metal Chelate Conjugated Dendrimer Constructs for Diagnosis and Therapy

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。为了弥补这一缺陷，我们实验室已经开发了基于树枝状大分子的磁共振造影剂，其中末端伯胺用螯合剂修饰，然后形成Gd(III)络合物。这些试剂的摩尔松弛系数是目前临床上使用的Gd(III)DTPA的6倍，比其他大分子试剂的两倍还要好。获得了良好的常规MR成像和3D T-O-F磁共振血管成像。研究已经扩大，以彻底探索这些制剂的效用。正在进行的小鼠模型系统实验证明，当使用G6代树枝状大分子构建时，完整的全身血管系统和作为血池试剂的成像非常详细。这些试剂还被评估为它们在小鼠模型中提供关于肿瘤血管系统的信息的能力。作为一个补充应用，这些试剂正在被评估为中子俘获治疗的目标，因为每个分子的Gd(III)密度很高，并且它们能够进入细胞。用于生产MRI造影剂的新型配基系统的开发仍在继续。最近成功地证明了Gd(III)杯[4]芳烃络合物可以通过与血清白蛋白的亲水相互作用来诱导和增强弛豫性能。计划包括制备和评价更稳定的Gd(III)，它也可以利用杯[4]芳烃的亲水相互作用能力。一种基于白蛋白与碘丙酸偶联的CT造影剂继续在临床前模型中进行评估，用于量化经颅间注射的治疗药物的流动和分散。这种材料正在与一种基于核磁共振白蛋白的试剂进行比较，目前正在准备准备将这种基于碘的试剂用于临床试验。使用树枝状大分子来制备一种完全合成的，因此一种可重复性的CT白蛋白试剂已经启动。G4代树枝状大分子接近白蛋白试剂的相对分子质量，但具有明显更多的反应性官能团，多碘CT造影剂可能通过这些官能团进行偶联。为此目的制备了一种Iopanic酸的水溶性类似物，并将其连接到G4树枝状分子上。对这种大分子的特性研究继续进行，以在任何体内评估之前确定目标产品，并与常规低分子CT造影剂进行比较。

Macromolecular agents composed of serum albumins or linear polymers have MRI contrast enhancement factors less than those predicted for rigid molecules of comparable size. To obviate this deficiency, MRI contrast agents based upon dendrimers, wherein terminal primary amines are modified with chelating agents that subsequently form Gd(III) complexes, have been developed in our laboratories. These reagents possess a molar relaxivity up to 6 times that of Gd(III)DTPA, currently employed in the clinic, and better than twice that of other macromolecular agents. Excellent conventional MR imaging and 3D T-O-F MR angiograms have been obtained. Studies have been expanded to thoroughly explore the utility of these agents. Ongoing experiments in a murine model system have demonstrated outstanding detailed imaging of the complete, whole-body vasculature and as blood-pool agents when using the G6 generation dendrimer construct. These reagents have also been evaluated for their ability to provide information concerning the tumor vasculature in murine models. As a complementary application, these reagents are being evaluated as Neutron Capture Therapy targets due to the high density of Gd(III) per molecule and their ability to cross into cells. The development of novel ligand systems for producing MRI contrast agents continues to proceed. The recent success of demonstrating that a Gd(III) calix[4]arene complex could induce and enhanced relaxivity by hydrophilic interaction with serum albumin continues to be pursued. Plans include the preparation and evaluation of more stable Gd(III) that also can take advantage of the hydrophilic interaction capacity of calix[4]arenes. A CT contrast agent based upon albumin conjugated to iopanoic acid continues to be evaluated in pre-clinical models for use in quantifying flow and dispersion of therapeutics being injected inter-cranially. This material is being compared to a MRI albumin-based reagent and preparations are underway to prepare the iodine-based reagent for use in clinical trials. Use of dendrimers to prepare a completely synthetic, and hence a reproducible analog of the CT albumin reagent has been initiated. Dendrimers of the G4 generation approach the MW of the albumin reagent, yet possess significantly greater numbers of reactive functional groups by which poly-iodinated CT contrast agents might be conjugated. A water soluble analog of iopanoic acid was prepared for this purpose and has been conjugated to the G4 dendrimeer. Characterization studies continue for this macromolecule to define the targeted products prior to any in vivo evaluation versus conventional low molecular weight CT contrast agents.