Metal Chelate Conjugated Dendrimer Constructs for Diagnosis and Therapy

用于诊断和治疗的金属螯合物共轭树枝状聚合物构建体

• 批准号: 6433409
• 负责人: MARTIN W BRECHBIEL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6433409
• 关键词: Rodentias; albumins; bismuth; chelating agents; chemical conjugate; computed axial tomography; contrast media; cytotoxicity; diagnosis design /evaluation; dogs; iodine; macromolecule; magnetic resonance imaging; neoplasm /cancer diagnosis; neoplasm /cancer therapy; polymers

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.

由血清白蛋白或线性聚合物组成的大分子药物的MRI对比增强因子小于相同大小的刚性分子的预测。为了消除这一缺陷，我们的实验室开发了基于树状大分子的MRI造影剂，其中末端伯胺被螯合剂修饰，随后形成Gd（III）复合物。这些试剂的摩尔弛豫度是目前临床使用的Gd(III)DTPA的6倍，是其他大分子试剂的两倍以上。获得了优秀的常规磁共振成像和3D T-O-F磁共振血管成像。研究已经扩展到彻底探索这些药物的效用。在小鼠模型系统中正在进行的实验表明，当使用G6代树突状结构时，可以对完整的全身血管系统进行出色的详细成像，并作为血池剂。这些试剂也被评估为它们在小鼠模型中提供有关肿瘤血管系统信息的能力。作为一种补充应用，由于每个分子中Gd（III）的高密度和它们进入细胞的能力，这些试剂正被评估为中子捕获治疗的靶标。用于生产MRI造影剂的新型配体系统的发展仍在继续。最近成功地证明了Gd（III）杯状[4]芳烃配合物可以通过与血清白蛋白的亲水性相互作用诱导和增强弛性。计划包括制备和评估更稳定的Gd(III)，也可以利用杯状[4]芳烃的亲水性相互作用能力。一种基于白蛋白与碘酸结合的CT造影剂继续在临床前模型中进行评估，用于定量脑内注射治疗药物的流量和分散。该材料正在与MRI白蛋白为基础的试剂进行比较，并且正在准备用于临床试验的碘为基础的试剂。利用树状大分子制备一种完全合成的，因此可重复的CT白蛋白试剂的类似物已经开始。G4代树状大分子接近白蛋白试剂的分子量，但具有明显更多的活性官能团，多碘CT造影剂可以通过这些官能团缀合。为此制备了一种可溶于水的碘酸类似物，并将其偶联到G4树突上。在与传统低分子量CT造影剂进行体内评估之前，对这种大分子进行表征研究，以确定目标产品。