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 基于Gd的造影剂(GBCA)使磁共振成像发生了革命性的变化。它们提供了对比和必要的 以其他方式无法获得的诊断信息。大约20年来，这些化合物一直是 被认为是最安全的药物之一。然而，在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)和 建立了肾损害患者的GBCA。自那以后，FDA对使用 肾功能受损患者的GBCA，几乎消除了NSF的风险；但保留了一些 患者无法获得潜在的挽救生命的对比增强磁共振成像。最近的报道说 即使在血脑屏障完好的患者体内，脑组织、骨骼和皮肤中也会累积沉积Gd。 而正常的肾和肝胆功能，具有未知的长期危险意义，已经引起了许多 科学界和患者的关切。在过去的几年里，我们在 基于立体负载大分子模板的无金属磁共振造影剂的研究进展 屏蔽的氮氧化物自由基。这些不含金属的核磁共振造影剂在体内表现出很高的疗效 在疾病组织(如肿瘤)中提供对比的能力。然而，当前的设计受到 体内氮氧自由基的不稳定，导致抗磁性羟胺减少。私家侦探的实验室有 最近报道了一种生物相容性很高的三芳甲基自由基的合成，具有无与伦比的体内稳定性， 命名为OX063。该自由基具有解决含氮有机自由基稳定性问题的能力 造影剂(ORCA)。此外，Ox063‘S的三价形状使其成为天然的树枝状大分子构筑块。在……里面 在这个项目中，我们建议开发基于OX063的树枝状大分子作为下一代无金属核磁共振 造影剂。在特定的目标1中，我们将合成并表征基于OX063的树枝状大分子作为双核磁共振 和荧光剂。一组虎鲸将装饰上与肿瘤相关的巨噬细胞结合 活性肿瘤靶向多肽。在特定目标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，以及活体成像验证。最后，在 具体目标3，我们将展示基于OX063的树枝状大分子在体内MRI肿瘤成像中的应用 在乳腺癌的小鼠模型中。我们将比较新虎鲸的主动和被动目标。这个 该项目的完成将提供高度生物稳定的不含金属的造影剂，这种造影剂可以显著影响 生物医学成像领域。