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.

由血清白蛋白或线性聚合物组成的大分子剂的MRI对比度增强因子小于相当大小的刚性分子所预测的。基于树枝状聚合物的MRI对比剂消除了这种缺陷。在我们的实验室中开发了用螯合GD（III）修饰的树状聚合物的末端胺。这些试剂具有GD（III）DTPA的6倍摩尔松弛度。已经获得了出色的常规全身MR成像和3D T-O-F MR血管造影。研究继续彻底探索这些药物的效用，并因此同时定义了它们的药代动力学和动力学。结果已经确定，这些大分子螯合剂基于树枝状聚合物的GD（III）MR对比剂可以通过调整调谐基本标准来调整各种应用：生成（MW和大小），核心元素（亲脂性和电荷），PEG CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-COM-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CO-CONECH给药（肾脏清除率）和与靶向载体的共轭（分子靶向）。基于PAMAM的药物已在200微米量表上精确成像鼠肿瘤脉管系统。基于DAB的药物具有选择性特性，其中检测到0.3 mM转移性肝肿瘤的反向对比图像。这些药物也不仅通过与抗体结合而有选择地针对目标，而且还通过其他载体（例如Avidin）将异常高水平的GD（III）（III）传递到分发腹膜内卵巢癌肿瘤中。最近的结果包括：（1）化学疗法诱导的肾脏毒性的评估，从而使肾脏受损的MRI图像与标准血液化学物质相关； （2）淋巴系统的成像，特别注意与淋巴瘤有关的淋巴结的参与； （3）将乳腺癌参与到淋巴结受累诊断中的乳腺癌参与到延端淋巴结中； （4）外束辐射对肿瘤脉管系统完整性的影响。最近对第一项研究进行了扩展以评估肾败血症损伤，并证明这种情况很容易区分再灌注损伤，而败血症也可以预测动物模型中败血症的死亡时间。第二和第三研究非常清楚地证明了基于树枝状聚合物的药物比小分子量剂的优势。通过MR成像以及正常小鼠中所涉及的淋巴管，自发发展乳腺癌的转基因小鼠以及在异种移植肿瘤轴承小鼠中的转基因小鼠清楚地定义了哨兵节点。研究的第四区域确定了肿瘤脉管系统对外束辐射的响应，其中打开了生物学“窗口”，从而可以通过肿瘤血管燃烧进行测量的泄漏。还确定了此“窗口”开口和关闭的TIMC课程动力学。建立了与大小和树枝状聚合物类别相关的PK/PD基准，我们现在开始从被动靶向的大分子MRI对比剂转向我们的研究中的下一个阶段，转向积极靶向的树枝状聚合物成像剂代理商。