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