Development of Long-circulating, Degradable Gd-Polyrotaxane MR Agents

长循环、可降解Gd-聚轮烷MR剂的研制

• 批准号: 8824207
• 负责人: DAVID H THOMPSON
• 金额: $ 20.35万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-29 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824207
• 关键词: Abbreviations; Acids; Address; Architecture; Biocompatible Materials; Blood; Cardiovascular system; Clinic; Complex; Contrast Media; Cyclodextrins; Dendrimers; Development; Diagnosis; Drug Kinetics; Family; Fibrosis; Filtration; Gadolinium; Glycolates; Hepatobiliary; Hydrolysis; Image; Ionizing radiation; Kidney; Lead; Ligands; Link; Liposomes; Magnetic Resonance Imaging; Medical Imaging; Metabolic Clearance Rate; Morphology; Neurologic; Organ; Pentetic Acid; Pluronics; Polymers; Polyrotaxanes; Positioning Attribute; Property; Protons; Relaxation; Resolution; Safety; Shapes; Site; Structure; Three-Dimensional Imaging; Time; Tissues; Toxic effect; Water; base; bioaccumulation; copolymer; design; flexibility; gadolinium 1,4,7,10-tetraazacyclododecane-N,N' ,N' ' ,N' ' ' -tetraacetate; gadolinium oxide; improved; interest; iron oxide; macrophage; nanoparticle; next generation; novel; particle; poly(lactic acid); polyrotaxane; public health relevance; retinal rods; scaffold; self assembly; tool; tumor; uptake

DESCRIPTION (provided by applicant): Magnetic Resonance Imaging (MRI) is a powerful tool for high-resolution three-dimensional (3D) medical imaging of anatomical structures and specific organs or tissues within the body. MRI has advantages such as an absence of ionizing radiation, high contrast, high spatial resolution and excellent depth profiling capabilities. The quality and contrast of MRI images can be improved by the use of MRI contrast agents that enhance the image contrast within the tissue of interest by altering the longitudinal (T1) and transverse (T2) relaxation rates of the surrounding water protons. Contrast agents can be classified into either T1 agents such as gadolinium (III) chelates, which increase the T1 relaxation rate and produce a positive image contrast, or T2 agents, such as supermagnetic iron oxide nanoparticles, which increase the T2 relaxation rate and produce a negative image contrast. A majority of clinically used contrast agents are Gd3+ chelates, which are favored due to their high paramagnetism, excellent relaxation enhancement, and stability. Unfortunately, most clinically approved contrast agents suffer from rapid clearance from the body and ineffective contrast enhancement hence making them ineffective for angiographic enhancement. In addition, the linear chelates of Gd3+ (e.g., DTPA) have been linked to safety problems related to nephrogenic systemic fibrosis in the clinic. Thus, the use of nanoparticles as carriers for contrast agents are attractive due to their long circulating properties and potential for tissu selectivity through the use of targeting ligands. Not only do such nanoparticles have better pharmacokinetics, they potentially can also carry a much higher Gd3+ loading. Unfortunately, most of the macromolecular and nanoparticle carriers to date suffer from safety issues such as poor renal filtration, hepatobiliary uptake, and bioaccumulation. Additionally, their synthesis and/or self-assembly restricts most of the materials to a spherical shape. We seek to develop long- circulating multivalent Gd3+ MRI contrast agents based on a degradable, flexible rod-like polyrotaxane (PR) scaffold that produces rapidly excreted, low toxicity hydrolysis products. The underlying hypothesis of the proposed polyrotaxane designs are that their flexible rod-like morphology would greatly enhance their pharmacokinetics by restricting macrophage uptake and rapid renal elimination, while providing control over their clearance rates through appropriate selection of the endcap linkages and/or polymer cores, thus addressing a major challenge in the development of next generation contrast media for MRI.

描述（由申请人提供）：磁共振成像（MRI）是一种强大的工具，用于对体内解剖结构和特定器官或组织进行高分辨率三维（3D）医学成像。 MRI具有无电离辐射、高对比度、高空间分辨率和出色的深度剖析能力等优点。 MRI 图像的质量和对比度可以通过使用 MRI 造影剂来提高，该造影剂通过改变周围水质子的纵向 (T1) 和横向 (T2) 弛豫率来增强感兴趣组织内的图像对比度。造影剂可分为 T1 剂（例如钆 (III) 螯合物）和 T2 剂（例如超磁性氧化铁纳米颗粒），前者可增加 T1 弛豫率并产生正图像对比度，后者可增加 T2 弛豫率并产生负图像对比度。临床上使用的造影剂大多为Gd3+螯合物，因其具有高顺磁性、优异的弛豫增强作用和稳定性而受到青睐。不幸的是，大多数临床批准的造影剂都存在从体内快速清除和无效的对比增强的问题，因此使得它们对于血管造影增强无效。此外，Gd3+的线性螯合物（例如DTPA）在临床上与肾源性系统性纤维化相关的安全问题有关。因此，使用纳米颗粒作为造影剂的载体是有吸引力的，因为它们具有长循环特性以及通过使用靶向配体实现组织选择性的潜力。此类纳米颗粒不仅具有更好的药代动力学，而且还可能携带更高的 Gd3+ 负载量。不幸的是，迄今为止，大多数高分子和纳米颗粒载体都存在安全问题，例如肾脏过滤不良、肝胆吸收和生物蓄积。此外，它们的合成和/或自组装将大多数材料限制为球形。我们寻求开发基于可降解、柔性棒状聚轮烷 (PR) 支架的长循环多价 Gd3+ MRI 造影剂，该支架可产生快速排泄、低毒的水解产物。所提出的聚轮烷设计的基本假设是，它们的柔性棒状形态将通过限制巨噬细胞摄取和快速肾脏消除来极大地增强其药代动力学，同时通过适当选择端盖连接和/或聚合物核心来控制其清除率，从而解决开发下一代MRI造影剂的主要挑战。