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: 7969807
• 负责人: MARTIN W BRECHBIEL
• 金额: $ 62.77万
• 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/7969807
• 关键词: Address; Amines; Angiography; Antibodies; Attention; Avidin; Back; Biological; Charge; Chelating Agents; Chemicals; Chemistry; Classification; Clinic; Clinical; Collaborations; Complement; Contrast Media; Dendrimers; Development; Diagnosis; Dyes; Electron Transport Complex III; Elements; Excision; Extramural Activities; Gadopentetate Dimeglumine; Generations; Goals; Heart; Image; Investigation; Laboratories; Legal patent; Liver neoplasms; Lymphatic; Lysine; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Metals; Modality; Modification; Molecular Target; Molecular Weight; Monitor; Monoclonal Antibodies; Mus; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Operative Surgical Procedures; Peptides; Pharmaceutical Preparations; Phase; Polymers; Property; Proteins; Radiology Specialty; Reagent; Renal clearance function; Research Personnel; Resolution; Resources; Running; Sentinel Lymph Node; Serum Albumin; Shapes; Site; Solvents; Surrogate Markers; Technology; Time; Toxic effect; Translating; Translations; analog; aqueous; base; chelation; imaging modality; instrumentation; interest; intraperitoneal; lipophilicity; molecular imaging; optical imaging; polypropyleneimine; programs; response; tumor; vector

Macromolecular MRI contrast agents based upon dendrimers obviate many of the deficiencies of serum albumin or linear polymer based MRI contrast agents of comparable size. This is due to the iterative polymeric synthesis by which they are created that then promotes a controlled size and shape of the dendrimer that concomitantly then provides the means for reproducible chemistry that is key to the clinical translation of such agents. To create MRI contrast agents with dendrimers, the 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 Magnevist, the currently approved MRI contrast agent. Excellent conventional whole body MR imaging and 3D T-O-F MR angiograms have been obtained with PAMAM and polypropyleneimine or DAB dendrimer based agents. Past results have established that macromolecular chelate conjugated dendrimer based Gd(III) MR contrast agents can be tuned for various applications by adjusting fundamental criteria: generation (MW & size), core elements (lipophilicity & charge), PEG conjugation, lysine co-administration (renal clearance), and conjugation to targeting 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 dendrimer based agents have also been 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. This study done in conjunction with an optical imaging agent runs in parallel with our creation of multi-modality dendrimer based imaging agents. The incorporation of a NIR optical imaging dye into the MRI agent to add an enhanced level of sensitivity to complement the resolution of the MRI imaging provided an additional level of sensitivity for the imaging of lymphatics and sentinel nodes that can be envisioned as being translated to an intraoperative scenario wherein MRI imaging and mapping would supplement real-time surgical intervention and excision of malignancy. While the chemistry established the ability to create such macromolecular agents, the imaging resulted in compromised targeting which defined that these agents require very careful systematic investigation combined with equally carefully defined characterization. Lastly, new chelation chemistry for conjugation of Gd(III) complexes to dendrimer has been prompted by the need to re-invent this filed moving it from aqueous chemistry back to organic phase solvents to enhance both characterization and consistency of yields. This chemistry has also evolved out of the need for specialized analogs of established bifunctional chelation agents to address the development of site-specific conjugation chemistry required for actively targeted dendrimer based imaging agents. In parallel to this effort, the very recent impact on NFS related Gd(III) toxicity of less than adequately stable MRI contrast agents prompted a complete halting of projects with an application of new directionality in the choice of bifunctional chelating agent at the heart of all of these studies. Thus, all ongoing projects were completed using the 1B4M-DTPA bifunctional chelate while all new projects were put on hold until adequate amounts of bifunctional DOTA became available through the synthesis efforts of the Section itself as opposed to purchase of this agent. While this effort was put into place over the past year, all of these projects have now moved over to use of a pre-complexation of the Gd(III) conjugation strategy using DOTA to eliminate a characterization complexity intended to simply translation of these agents into clinical use. Results from the studies to validate this transformation have revealed that not only can such a strategy be employed, but that far greater molar relaxivity can be achieved by this means. The exquisite advantages of the dendrimer based agents over low molecular weight agents continue to be very clearly demonstrated. In parallel to the development of dendrimer based agents, a long-term collaboration with NINDS investigators to develop a surrogate marker for CED of chemotherapeutic drugs continues to move forward with all of the above noted chemical modifications included to advance this technology into the clinic in the safest format possible. A US patent covering this technology was issued this year and is attracting considerable attention and interest that should contribute to translation of this technology into the clinic. Studies of MRI and other imaging modality agents in collaboration with the Molecular Imaging Program have unfortunately been effectively terminated due to a lack of cooperation and access to instrumentation residing therein what was to be a resource for all NCI researchers. However, collaboration with Radiology, CC, the PER Dept, CC, and NIMH , and extramural researchers have replaced the Molecular Imaging Program, NCI.

基于树枝状聚合物的大分子MRI造影剂包括许多 血清白蛋白或线性聚合物类MRI造影剂的不足。 这是由于迭代聚合物合成，通过该聚合物合成，它们被创建，然后促进 树枝状聚合物的受控尺寸和形状，其随之提供了用于 可重复的化学是这些药物临床转化的关键。创建MRI 具有树枝状聚合物的造影剂，树枝状聚合物的末端伯胺用 螯合Gd（III）是在我们的实验室中开发的。这些试剂具有摩尔弛豫率 是目前批准的MRI造影剂Magnevist的6倍。优秀的传统 已使用PAMAM获得全身MR成像和3D T-O-F MR血管造影， 聚丙烯亚胺或DAB树枝状聚合物基试剂。过去的结果表明， 基于大分子螯合物共轭树枝状聚合物的Gd（III）MR造影剂可以被调整用于 通过调整基本标准：发电量（MW大小）， 核心元件（亲脂性电荷）、PEG结合、赖氨酸共同给药 （肾清除）和与靶向载体缀合（分子靶向）。基于PAMAM 这些试剂已经在200微米尺度上精确地成像了鼠肿瘤脉管系统。基于DAB 试剂具有选择性，其中0.3 mm转移性肝的反向对比图像 检测到肿瘤。这些基于树枝状聚合物的试剂也被选择性地靶向，而不是靶向。 仅通过与抗体缀合，但通过其他载体，如抗生物素蛋白， 异常高水平的Gd（III）进入播散性腹膜内卵巢癌肿瘤。 这项研究与光学成像剂一起进行，与我们的研究并行进行。 基于多模态树枝状聚合物的成像剂的产生。近红外光学的结合 将成像染料添加到MRI试剂中以增加增强的灵敏度水平，以补充 MRI成像的分辨率为以下成像提供了额外的灵敏度水平： 可以设想将淋巴结和前哨淋巴结转移到术中 MRI成像和标测将补充实时手术干预的情况， 恶性肿瘤切除术。虽然化学物质建立了创造这种 大分子药物，成像导致受损的靶向，这定义了这些 代理商需要非常仔细的系统调查， 特征化最后，新的螯合化学用于缀合Gd（III）络合物， 树枝状聚合物已促使需要重新发明这一领域移动它从水 化学回到有机相溶剂，以提高表征和一致性， 收益率这种化学物质也是从对特定的已建立的类似物的需要中发展出来的。 双功能螯合剂，以解决位点特异性缀合的发展 基于主动靶向树枝状聚合物的成像剂所需的化学性质。与此并行地 努力，最近对NFS相关的Gd（III）毒性的影响不够稳定 MRI造影剂促使项目完全停止， 在所有这些的核心双功能螯合剂的选择方向性 问题研究因此，使用1B 4 M-DTPA双功能螯合物完成了所有正在进行的项目 而所有新项目都被搁置，直到足够数量的双功能DOTA成为 可通过该科本身的综合努力获得，而不是购买 剂虽然这项工作是在过去一年中进行的，但所有这些项目现在都已完成。 转移到使用DOTA的Gd（III）缀合策略的预络合的使用， 消除了旨在简单地将这些试剂翻译成 临床应用。验证这种转变的研究结果表明， 只有这样的策略才能被采用，但是通过以下方式可以实现更大的摩尔弛豫率： 这意味着。基于树枝状聚合物的药剂相对于低分子量药剂的显著优势 代理人继续非常清楚地证明。与树枝状聚合物的发展平行 基于代理，与NINDS研究人员长期合作，开发替代标记物 化疗药物的CED继续向前发展， 包括化学修饰，以最安全的方式将这项技术推向临床。 格式可能。今年发布了一项涵盖这项技术的美国专利， 相当大的关注和兴趣，应有助于翻译这项技术 进了诊所MRI和其他成像方式试剂的研究， 分子成像计划已经不幸地被有效地终止，由于缺乏 合作和使用其中的仪器，这将是所有人的资源 NCI研究人员。然而，与放射科、CC、PER部门、CC和NIMH的合作，以及 校外研究人员已经取代了NCI的分子成像项目。