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: 8350068
• 负责人: MARTIN W BRECHBIEL
• 金额: $ 59.18万
• 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/8350068
• 关键词: Address; Agreement; Albumins; Alkynes; Amines; Angiography; Antibodies; Avidin; Azides; Back; Biological; Blood Circulation; CCR; Charge; Chelating Agents; Chemistry; Clinic; Clinical; Collaborations; Complement; Contrast Media; Dendrimers; Development; Diagnosis; Drug usage; Dyes; Electron Transport Complex III; Elements; Excision; Extramural Activities; Gadopentetate Dimeglumine; Generations; Goals; Heart; Image; Imaging technology; Investigation; Laboratories; Legal patent; Liver; Liver neoplasms; Lymphatic; Lysine; Magnetic Resonance Imaging; Maleimides; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Metals; Modality; Molecular Target; Molecular Weight; Monitor; Monoclonal Antibodies; Mus; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; Operative Surgical Procedures; Organ; Pentetic Acid; Peptides; Phase; Polymers; Positron-Emission Tomography; Property; Publications; Radiology Specialty; Reagent; Renal clearance function; Reporting; Reproducibility; Research Personnel; Resolution; Resources; Running; Safety; Science; Sentinel Lymph Node; Serum Albumin; Shapes; Site; Solubility; Solvents; Sulfhydryl Compounds; Surrogate Markers; Technology; Time; Toxic effect; Translating; Translations; Work; analog; aqueous; base; chelation; imaging modality; instrumentation; interest; intraperitoneal; lipophilicity; molecular imaging; novel; optical imaging; polypropyleneimine; programs; response; single photon emission computed tomography; sound; tumor; uptake; 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 concomitantly generating 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 are modified with chelated Gd(III) developed in our laboratories. Historically, these reagents were shown to 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 studies 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 (prolong circulation and minimize liver and other organ uptake), 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 careful defined characterization. Lastly, new chelation chemistry for conjugation of Gd(III) complexes to dendrimer has been prompted by the need to re-invent this field 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 e.g, maleimides targeting a unique thiol residue, or agents functionalized with alkyne and azide groups for click chemistry conjugation strategies. In parallel to this effort, the very recent impact on NFS related Gd(III) toxicity of less than adequately stable MRI contrast agents that had prompted a complete halt of projects with an application of new directionality in the choice of bifunctional chelating agent at the heart of all of these studies has resulted in redirection of all such projects with the use of DOTA as the bifunctional chelating agent, however with the Gd(III) complex pre-formed prior to conjugation to all targeting vectors. While this effort was put into place over the past 2 years, all of the MR contrast projects have now migrated to the exclusive use of a pre-complexation of the Gd(III) conjugate strategy using DOTA to eliminate a characterization complexity resulting from the creation of exceedingly difficult to characterize mixtures of product that limited reproducibility of agents that would have complicated 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 successfully employed despite warnings of probably lowered solubility (not true), but that far greater molar relaxivity can be achieved by this means. We have reported a 5-fold enhancement over the prior technology while concurrently decreasing the actual physical amount of Gd(III) conjugated to the dendrimer by 65%. The impact of this result should reach across to all macromolecular MR contrast agents regardless of platform to fully address safety, characterization, and reproducibility thereby furthering an entire fields potential for clinical translation of such agents. The exquisite advantages of the dendrimer based agents over low molecular weight agents continue to be very clearly demonstrated. In parallel to this improvement to abrogate toxicity concerns that has resulted in superior dendrimer based agents, the collaboration with NINDS developing a surrogate marker for CED of chemotherapeutic drugs using an albumin core platform was terminated vs. continuing with the less safe DTPA chemistry. While regrettable, the Chemistry Section always opts to pursue fundamentally sound and reproducible science and chemistry that permits advancing technology into the clinic in the safest format possible using a safe agent as opposed to knowingly participating in studies that might employ an unsafe agent. Regardless of this disappointment, the Chemistry Section continued the investigation independently to validate the use of the above strategy and a report has been submitted for publication on those results. The US patent covering this technology was issued last year and these new results, particularly those related to its application to an albumin core, should prove to make it yet more valuable to HHS and should also 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 terminated due to a lack of cooperation and access to instrumentation residing therein in what was to be a resource for all NCI researchers despite agreements to the contrary. However, established collaborations with Radiology, CC, the PET Dept, CC, NIMH, and extramural researchers continue to be fruitful.

基于树枝状聚合物的大分子MRI对比剂消除了血清白蛋白或线性聚合物基于线性聚合物的MRI对比剂的许多缺陷。这是由于迭代聚合物的合成所致，通过它们创建它们，然后促进树突聚合物的受控大小和形状，同时产生了可再现化学的平均值，这是此类药物临床翻译的关键。为了创建与树突聚合物的MRI对比剂，树枝状聚合物的末端原发胺通过我们的实验室中开发的螯合GD（III）进行了修饰。从历史上看，这些试剂被证明具有摩尔松弛性的6倍，这是当前已批准的MRI对比剂的Magnevist。使用PAMAM和聚丙烯酰胺或基于DAB树状聚合物的剂获得了出色的常规全身MR成像和3D T-O-F MR血管造影。 Past studies 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 (prolong circulation and minimize liver and other organ uptake), lysine co-administration (renal clearance), and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的剂具有选择性特性，其中检测到0.3 mM转移性肝肿瘤的反对比图像。 这些基于树枝状聚合物的剂也是选择性的，不仅是通过与抗体结合来选择性的，而且还通过其他载体（例如Avidin）将异常高水平的GD（III）（III）传递到传播的腹膜内卵巢癌肿瘤中。这项与光学成像剂结合进行的研究与我们创建的基于多模式树枝状聚合物的成像剂并行运行。 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.虽然化学基础建立了创建这种大分子药物的能力，但成像导致靶向损害，这确定了这些药物需要非常仔细的系统研究，并结合了同样仔细的定义表征。 最后，由于需要将其从水性化学反应到有机相位溶剂，以增强其表征和产量的一致性，因此已经提示了将GD（III）复合物与树枝状聚合物结合的新螯合化学。这种化学也出于需要对已建立双功能性螯合剂的专业类似物的需求，以应对基于积极靶向的基于树突的成像剂所需的现场特异性共轭化学的开发，例如针对独特的硫醇残留物的MaleImides，或与Alkyne和Azide Clips Chips Chemive Chemjugations Conjugugations Conconjugugations of Unique Thiol残留物，或者针对独特的硫醇残留物。 与这项努力的并联，最近对NFS相关的GD（III）毒性的影响不足，其稳定的MRI对比代理促使所有这些研究都与所有这些研究的核心相对于所有这些项目的核心促进了全新的方向性的完全停止，但是与dota As the Chementional的所有这些项目相关联，该项目的使用均与dota As t e extirational congentii rughtations一起。在与所有靶向矢量结合之前进行了预制。 While this effort was put into place over the past 2 years, all of the MR contrast projects have now migrated to the exclusive use of a pre-complexation of the Gd(III) conjugate strategy using DOTA to eliminate a characterization complexity resulting from the creation of exceedingly difficult to characterize mixtures of product that limited reproducibility of agents that would have complicated translation of these agents into clinical use. 研究结果验证这种转变的结果表明，尽管警告说可能降低了溶解度（不是真的），但不仅可以成功地采用这种策略，而且通过这种方式可以实现更大的摩尔松弛性。我们报道了对先前技术的增强，同时减少了与树枝状聚合物相连的GD（III）的实际物理量，降低了65％。该结果的影响应涉及所有大分子MR对比剂剂，而不管平台如何完全解决安全性，表征和可重复性，从而进一步推动了整个领域的临床转换潜力。基于树枝状聚合物的药物比低分子量剂的精致优势仍然非常清楚地证明。 同时，通过消除毒性问题的改善，这导致了基于树枝状聚合物的剂量，与Ninds合作使用白蛋白核心平台开发了化学治疗药物CED的替代标记，终止了与较不安全的DTPA化学的终止。尽管令人遗憾，化学部分始终选择从根本上进行健全和可重复的科学和化学，这些科学和化学允许使用安全的药物以最安全的形式前进技术，而不是故意参与可能采用不安全代理的研究。 不管这一失望如何，化学部门继续进行了独立的调查，以验证上述战略的使用，并已提交了有关这些结果的报告。去年发布了涵盖这项技术的美国专利专利，这些新结果，特别是与其在白蛋白核心上的应用相关的结果，应该证明它使其对HHS更有价值，并且还应该有助于将该技术转化为诊所。 不幸的是，由于缺乏合作和访问该仪器的访问，对MRI和其他成像模式与分子成像程序合作的研究已被终止。但是，与放射学，CC，PET部，CC，NIMH和壁外研究人员建立了合作。