Biocompatible triarylmethyl radical-based dendrimers as nonmetallic contrast agents for MRI

生物相容性三芳基甲基自由基树枝状聚合物作为 MRI 非金属造影剂

• 批准号: 10655658
• 负责人: Benoit Driesschaert
• 金额: $ 38.9万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655658
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Animal Cancer Model; Binding; Blood - brain barrier anatomy; Brain; Breast Cancer Model; Cancer Model; Chemistry; Chronic Kidney Failure; Circulation; Clinic; Communities; Compensation; Contrast Media; Dendrimers; Deposition; Development; Diagnostic; Disease; Dose; Drug Kinetics; Excretory function; Fibrosis; Fluorescence; Fluorescent Dyes; Future; Gadolinium; Generations; Hepatobiliary; High Risk Woman; Hydroxylamine; Image; Impairment; In Vitro; Injections; Kidney; Lead; Life; Ligands; Liquid substance; MRI Scans; Magnetic Resonance Imaging; Manganese; Medical; Metabolism; Metals; Modeling; Modification; Names; Nephrogenic Systemic Fibrosis; Patient Agents; Patients; Peptides; Performance; Pharmacologic Substance; Phase; Physicians; Polymers; Pre-Clinical Model; Prognosis; Property; Protocols documentation; Recommendation; Renal function; Reporting; Risk; Safety; Scientist; Shapes; Skin; Solid; Surface; Therapeutic Agents; Tissues; Toxic effect; Toxicology; Tumor-associated macrophages; Validation; Work; biomaterial compatibility; biomedical imaging; bone; cancer imaging; chelation; contrast enhanced; design; diagnostic tool; diagnostic value; experience; hazard; hydrophilicity; imaging capabilities; imaging modality; improved; in vivo; in vivo imaging; interest; iron oxide nanoparticle; malignant breast neoplasm; mouse model; near infrared dye; next generation; nitroxyl; optical imaging; organic base; radiologist; scaffold; superparamagnetism; theranostics; tumor; virtual

ABSTRACT Gadolinium-based contrast agents (GBCA) have revolutionized MRI. They provide contrast and essential diagnostic information that could not be obtained otherwise. For about 20 years, these compounds were considered among the safest pharmaceuticals. However, in 2006 the causal relationship between the development of a devastating and potentially fatal condition named nephrogenic systemic fibrosis (NSF) and GBCAs in renocompromized patients was established. The FDA has since placed restrictions on the use of GBCAs for patients with impaired kidney function, virtually eliminating the risk of NSF; however leaving some patients without having access to potentially lifesaving contrast-enhanced MRI. The more recent reports that gadolinium deposits cumulatively in the brain, bones, and skin, even in patients with intact blood-brain-barrier and normal renal and hepatobiliary functions, with unknown long-term hazard significance, have raised many concerns among the scientific community and patients. The last few years have seen breakthroughs in the development of metal-free MRI contrast agents based on macromolecular templates loaded with sterically shielded nitroxide radicals. These metal-free MRI contrast agents have demonstrated high efficacy in vivo with the ability to provide contrast in disease tissues (e.g., tumors). However, the current designs are limited by the instability of nitroxides radicals in vivo, leading to reduced diamagnetic hydroxylamines. The PI's lab has recently reported the synthesis of a highly biocompatible triarylmethyl radical with unmatched in vivo stability, named OX063. This radical has the capability to solve the stability issues of nitroxide-based organic radical contrast agents (ORCA). Moreover, Ox063’s trivalent shape makes it a natural dendrimer building block. In this project, we propose to develop OX063-based dendrimers as the next generation of metal-free MRI contrast agents. In specific aim 1, we will synthesize and characterize OX063-based dendrimers as dual MRI and fluorescent agents. A set of ORCAs will be decorated with a tumor-associated macrophage-binding peptide for active tumor targeting. In specific aim 2, we will perform in vitro and in vivo distribution, metabolism, excretion, toxicology, and pharmacokinetic studies, and in vivo imaging validation. Finally, in specific aim 3, we will demonstrate the application of OX063-based dendrimers for in vivo MRI tumor imaging in a mouse model of breast cancer. Active and passive targeting of the new ORCAs will be compared. The completion of the project will provide highly biostable metal-free contrast agents which can significantly impact the field of biomedical imaging.

摘要 钆基造影剂（GBCA）彻底改变了MRI。它们提供了对比， 否则无法获得的诊断信息。大约20年来，这些化合物 被认为是最安全的药物之一。然而，2006年， 发展为一种破坏性和潜在致命的疾病，称为肾源性系统性纤维化（NSF）， 建立了肾功能损害患者的GBCA。此后，FDA限制了 GBCA用于肾功能受损患者，几乎消除了NSF的风险;然而， 无法获得潜在救命的对比增强MRI的患者。最近的报道说， 钆在脑、骨和皮肤中累积沉积，甚至在血脑屏障完整的患者中也是如此 以及正常的肾脏和肝胆功能，其长期危害意义未知，引发了许多 科学界和患者的担忧。在过去的几年里， 基于大分子模板的无金属MRI造影剂的开发 屏蔽氮氧自由基。这些不含金属的MRI造影剂已经在体内表现出高功效， 在疾病组织中提供对比的能力（例如，肿瘤）。然而，目前的设计受到限制， 体内氮氧自由基的不稳定性，导致抗磁性羟胺减少。私家侦探的实验室 最近报道了具有无与伦比的体内稳定性的高度生物相容的三芳基甲基自由基的合成， 代号OX 063该自由基具有解决氮氧自由基稳定性问题的能力 造影剂（ORCA）。此外，Ox 063的三价形状使其成为天然的树枝状聚合物结构单元。在 在这个项目中，我们建议开发基于OX 063的树枝状聚合物作为下一代无金属MRI 造影剂。在具体目标1中，我们将合成并表征基于OX 063的树枝状聚合物作为双MRI 和荧光剂。一组ORCA将用肿瘤相关的巨噬细胞结合蛋白修饰， 用于主动肿瘤靶向的肽。在具体目标2中，我们将进行体外和体内分布， 代谢、排泄、毒理学和药代动力学研究以及体内成像验证。最后在 具体目标3，我们将展示基于OX 063的树枝状聚合物在体内MRI肿瘤成像中的应用 在一个乳腺癌的小鼠模型中。将比较新ORCA的主动和被动靶向。的 该项目的完成将提供高度生物稳定的无金属造影剂， 生物医学成像领域。