Metal Chelate Conjugated Dendrimer Constructs for Diagno

用于诊断的金属螯合物共轭树枝状聚合物构建体

• 批准号: 7068878
• 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/7068878
• 关键词: bioimaging /biomedical imaging; breast neoplasms; chelating agents; chemical conjugate; contrast media; diagnosis design /evaluation; drug adverse effect; drug delivery systems; gadolinium; kidney imaging /visualization; liver neoplasms; lymphatic system; macromolecule; magnetic resonance imaging; neoplasm /cancer blood supply; neoplasm /cancer diagnosis; neoplasm /cancer radionuclide therapy; neutron radiation; transfection /expression vector

Macromolecular agents composed of serum albumin or linear polymers have MRI contrast enhancement factors less than those predicted for rigid molecules of comparable size. MRI contrast agents based upon dendrimers obviate this deficiency. Terminal primary amines of dendrimers modified with chelated Gd(III) are developed in our laboratories. These reagents possess a molar relaxivity 6 times that of Gd(III)DTPA. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained. Studies continue to thoroughly explore the utility of these agents and to thus simultaneously define their pharmacokinetics and dynamics. Results have established that these macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents can be tuned for various applications by adjusting tuning fundamental criteria: generation (MW and size), core elements (lipophilicity and charge), PEG conjugation, lysine co-administration (renal clearance), and conjugation to targetng vectors (molecular targeting). PAMAM based agents have imaged murine tumor vasculature accurately at the 200 micron scale. DAB based agents have selective properties wherein reverse contrast images of 0.3 mm metastatic liver tumors were detected. These agents have also beenc selectively targeted, not only by conjugation to antibodies, but by other vectors, such as avidin to deliver exceptionally high levels of Gd(III) into disseminated intraperitoneal ovarian cancer tumor. Recent results include: (1) assessment of chemotherapy induced renal toxicity whereby the MRI images of damaged kidney correlate with standard blood chemistries; (2) imaging of the lymphatic system with particular attention to involvement of the lymph nodes relating to lymphoma; (3) imaging of breast cancer involvement with drainage to sentinal nodes for lymph node involvement diagnosis; and (4) effects of external beam radiation on the integrity of tumor vasculature. The first study has recently been extended to evaluate renal sepsis injury and demonstrated that this type of condition could be easily differentiate between reperfusion injury, and sepsis that was also predictive of time to death from sepsis in the animal model. The second and third studies very clearly demonstrated the exquisite advantages of the dendrimer based agents over small molecular weight agents. Draining sentinel nodes were clearly defined by MR imaging along with the involved lymphatic vessels in normal mice, transgenic mice that spontaneously develop breast cancer, and in xenograft tumor bearing mice. The fourth area of study determined the response of tumor vasculature to external beam radiation wherein a biological "window" was opened permitting the measured leakage through tumor vessel fenestrations. The timc course kinetics of the opening and closing of this "window" was also determined. Having established PK/PD baselines correlative with size and class of dendrimer, we now proceed to move forward from passively targeted macromolecular MRI contrast agents to the next phase of in our study to actively targeted dendrimer based imaging agents that may also be multi-modality imaging agents.

由血清白蛋白或线状聚合物组成的大分子药物，其MRI对比增强因子比同等大小的刚性分子预测的要小。基于树突分子的MRI造影剂消除了这一缺陷。用螯合Gd（III）修饰的树状大分子末端伯胺是在我们的实验室开发的。这些试剂的摩尔弛豫率是Gd(III)DTPA的6倍。获得了良好的常规全身磁共振成像和3D T-O-F磁共振血管成像。研究继续深入探索这些药物的效用，从而同时确定它们的药代动力学和动力学。结果表明，这些基于螯合物的大分子共轭树突状分子Gd(III) MR造影剂可以通过调整基本标准来调整各种应用：生成（分子量和大小）、核心元素（亲脂性和电荷）、PEG偶联、赖氨酸共给药（肾脏清除）和偶联到靶向载体（分子靶向）。基于PAMAM的药物可以在200微米尺度上精确成像小鼠肿瘤血管系统。基于DAB的试剂具有选择性，其中0.3 mm转移性肝肿瘤的反向对比图像被检测到。这些药物也被选择性靶向，不仅通过与抗体结合，而且通过其他载体，如亲和素，将异常高水平的Gd（III）递送到弥散性腹腔内卵巢癌肿瘤中。最近的研究结果包括：(1)评估化疗引起的肾毒性，其中受损肾脏的MRI图像与标准血液化学相关；(2)淋巴系统影像学检查，特别注意与淋巴瘤有关的淋巴结受累情况；(3)乳腺癌累及前哨淋巴结引流的影像学诊断；(4)外束辐射对肿瘤血管完整性的影响。第一项研究最近被扩展到评估肾脓毒症损伤，并证明这种类型的情况可以很容易地区分再灌注损伤和脓毒症，并且在动物模型中也可以预测脓毒症的死亡时间。第二和第三项研究非常清楚地证明了基于树突状分子的药剂相对于小分子量药剂的优越优势。在正常小鼠、自发发展为乳腺癌的转基因小鼠和异种移植荷瘤小鼠中，MR成像清楚地定义了引流前哨淋巴结以及受累的淋巴管。研究的第四个领域确定了肿瘤血管对外部光束辐射的反应，其中打开了一个生物“窗口”，允许通过肿瘤血管开窗测量泄漏。还确定了该“窗口”的打开和关闭的时间过程动力学。在建立了与树突状分子大小和类别相关的PK/PD基线后，我们现在继续从被动靶向大分子MRI造影剂进入我们研究的下一阶段，即主动靶向树突状分子造影剂，也可能是多模态造影剂。