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.

抽象的 基于Gadolinium的对比剂（GBCA）彻底改变了MRI。他们提供对比和必不可少的 否则无法获得的诊断信息。大约20年，这些化合物是 被认为是最安全的药物之一。但是，在2006年， 开发毁灭性和潜在的致命状况，称为肾病全身纤维化（NSF）和 建立了培育代表患者的GBCA。此后，FDA已对使用的限制 肾功能受损患者的GBCA，实际上消除了NSF的风险；但是留下了一些 患者无权获得潜在的救生对比增强的MRI。最近的报道说 Gadolinium在大脑，骨骼和皮肤中累积沉积，即使在具有完整的血脑屏障患者中 正常的肾脏和肝胆功能，具有未知的长期危害意义，已经提高了许多 科学界和患者的担忧。最近几年在 开发基于大分子模板的无金属MRI对比剂的开发 屏蔽的氮氧化物自由基。这些无金属MRI对比剂在体内表现出很高的效率 在疾病组织（例如肿瘤）中提供对比度的能力。但是，当前的设计受到 氮氧化物自由基在体内的不稳定性，导致降低二磁羟胺。 Pi的实验室有 最近报道了高度生物相容性三甲基自由基的合成，并具有无与伦比的体内稳定性， 命名为OX063。这种激进的能力可以解决基于硝基的有机基机的稳定性问题 对比剂（ORCA）。此外，OX063的三价形状使其成为天然的树枝状聚合物构建块。在 这个项目，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 对比剂。在特定的目标1中，我们将合成并将基于OX063的树枝状聚合物作为双MRI表征 和荧光剂。一组逆戟鲸将用肿瘤相关的巨噬细胞结合装饰 用于活性肿瘤靶向的肽。在特定的目标2中，我们将在体外和体内分布执行， 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，我们将证明基于OX063的树枝状聚合物在体内MRI肿瘤成像中的应用 在乳腺癌的小鼠模型中。将比较新兽人的主动和被动靶向。这 该项目的完成将提供高度可生物可生物的金属对比度剂，这可能会对 生物医学成像领域。