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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的钆基造影剂 (GBCA) 彻底改变了 MRI，它们提供造影剂和必要的造影剂。大约 20 年来，这些化合物一直是无法通过其他方式获得的诊断信息。被认为是最安全的药品之一，但是，2006 年之间存在因果关系。一种称为肾源性系统性纤维化 (NSF) 的破坏性且可能致命的疾病的发展，以及自此，FDA 开始限制 GBCA 在肾功能不全患者中的使用。 GBCA 用于肾功能受损的患者，实际上消除了 NSF 的风险，但仍留下一些风险；患者无法获得可能挽救生命的对比增强磁共振成像。即使在血脑屏障完整的患者中，钆也会累积沉积在大脑、骨骼和皮肤中正常的肾功能和肝胆功能，其长期危害意义未知，引起了许多关注科学界和患者的担忧在过去几年中取得了突破。基于空间负载大分子模板的无金属MRI造影剂的开发这些不含金属的 MRI 造影剂已在体内表现出高效能。在疾病组织（例如肿瘤）中提供对比的能力然而，当前的设计受到限制。体内硝基氧自由基的不稳定性，导致抗磁性羟胺的减少。最近报道了一种高度生物相容性的三芳基甲基自由基的合成，该自由基具有无与伦比的体内稳定性，该自由基被命名为OX063，能够解决氮氧自由基的稳定性问题。此外，Ox063 的三价形状使其成为天然的树枝状聚合物构建单元。在这个项目中，我们建议开发基于 OX063 的树枝状聚合物作为下一代无金属 MRI 在具体目标 1 中，我们将合成基于 OX063 的树枝状聚合物并将其表征为双 MRI。一组 ORCA 将被肿瘤相关巨噬细胞结合修饰。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。具体目标3，我们将展示基于OX063的树枝状大分子在体内MRI肿瘤成像中的应用将在乳腺癌小鼠模型中对新 ORCA 的主动和被动靶向进行比较。该项目的完成将提供高度生物稳定的无金属造影剂，这可以显着影响生物医学成像领域。