ANALYSIS OF DENDRIMER BASED MRI CONTRAST AGENTS

该项目的长期目标是开发磁共振成像技术 (MRI)造影剂，将改善乳腺癌的诊断和减少 乳腺癌患者的长期发病率。 许多已知 与癌症相关的细胞变化可以影响 控制药物或造影剂的血液到组织的运输。 动态 磁共振乳腺摄影（MRM）利用这些细胞的变化只有一个 与癌症相关：肿瘤分泌的血管生成因子。 我们建议 利用其他变化，肿瘤分泌血管通透性 因素，以改善检测，诊断，和/或治疗，通过增强 渗透性和保持效果。 该项目有四个具体目标。 首先，我们将确定 影响大分子MRI有效性的理化性质 由Starburst树枝状聚合物制备的造影剂，以及第二制备 具有最佳相关性的大分子造影剂， 药物动力学和生物学特性的被动和主动 靶向乳腺肿瘤。 三是发展细胞外液 具有较高弛豫率和稍微延长半衰期的隔离剂， 改善动态对比增强MRM。 最后的具体目标是 测定健康大鼠的体内药代动力学和生物分布 和那些化学诱导的乳腺肿瘤。 作为这一目标的一部分，我们 将确定乳腺肿瘤是否表现出增强的渗透性， 与正常组织相比， 影响这种吸收的物理化学性质。 我们将2-（4-异硫氰酸基苄基）-6- 甲基二亚乙基三胺五乙酸和2-（4 '-异硫氰酸根合苄基）- 1，4，7，10-四氮杂环十二烷-N，N '，N”，N'“-四乙酸到树枝状聚合物 在尺寸、内部密度和表面基团的密度上不同。 本文测量了三种晶体的核磁弛豫色散剖面， Gd（III）-配合物的电子顺磁共振研究 VO（II）-络合物的电子顺磁弛豫色散曲线 Gd（III）-配合物的核磁共振研究 在5%H217O中的复合物将提供关于tr tau tau和tv 影响这些药剂的松弛性。 乳腺肿瘤的诱导 将继续注射高剂量（180 mg/kg）的N-乙基-N- 亚硝基脲注射到30日龄雌性Sprague道利大鼠体内。 体内结果 将通过注射获得药代动力学和生物分布 示踪量的155 Gd（III）结合到这些树枝状聚合物-多螯合物。 对比增强动力学将在1.5和1.5下在肿瘤上获得。 4.7T. 这些信息将使合理设计的有效 用于乳腺诊断的被动或抗原导向MR造影剂 癌症和其他疾病。

The long term goal of this project is to develop magnetic resonance imaging (MRI) contrast agents that will improve breast cancer diagnosis and reduce the long term morbidity of breast cancer patients. A number of known cellular changes associated with cancer can effect the parameters that control the blood-to-tissue transport of a drug or contrast agent. Dynamic MR mammography (MRM) takes advantage of only one of these cellular changes associated with cancer: tumor secreted angiogenic factors. We propose to take advantage of other changes, tumor secreted vascular permeability factors, to improve detection, diagnosis, and/or treatment via the enhanced permeability and retention effect. The project has four specific aims. First we will determine the physiochemical properties that influence the efficacy of macromolecular MRI contrast agents prepared from Starburst Dendrimers, and second prepare macromolecular contrast agents with the optimal relativity, pharmacokinetics, and biological properties for both the passive and active targeting to breast tumors. The third is to develop extracellular fluid space agents with higher relaxivities and slightly prolonged half-lives for improving dynamic contrast enhanced MRM. The final specific aim is to determine the in vivo pharmacokinetics and biodistributions in healthy rats and those with chemically induced breast tumors. As part of this aim we will determine if breast tumors express an enhanced permeability and retention of dendrimer-based agents, compared with normal tissue, and the physicochemical properties that influence this uptake. We will attach 2-(4-isothiocyanatobenzyl)-6- methyldiethylenetriaminepentaacetic acid, and 2-(4'-isothiocyanatobenzyl)- 1,4,7,10-tetraazacyclodoecane-N, N', N", N'"-tetraacetic acid to dendrimers differing in size, interior density, and the density of the surface groups. Measurements of the nuclear magnetic relaxation dispersion profiles of the Gd(III)-complexes, the electron paramagnetic resonance studies of the VO(II)-complexes, the electron paramagnetic relaxation dispersion profiles of Gd(III)-complexes, and O nuclear magnetic resonance studies of Gd(III)- complexes in 5% H217O will provide the data on how tr tau tau and tv influence the relaxtivity of these agents. Induction of the breast tumors will proceed with the injection of high doses, 180 mg/kg, of N-ethyl-N- nitrosourea into 30 d old female Sprague Dawley rats. In vivo results on the pharmacokinetics and biodistribution will be obtained by the injection of tracer amounts of 155 Gd(III) bound to these dendrimer-polychelates. Contrast enhancement kinetics will be obtained on the tumors at 1.5 and 4.7T. This information will enable the rational design of effective passive or antigen directed MR contrast agents for the diagnosis of breast cancer and other pathologies.