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

描述（由申请人提供）：磁共振成像（MRI）是对人体解剖结构和特定器官或组织进行高分辨率三维（3D）医学成像的强大工具。MRI具有无电离辐射、高对比度、高空间分辨率和出色的深度成像能力等优点。MRI造影剂可以通过改变周围水质子的纵向（T1）和横向（T2）弛豫速率来增强感兴趣组织内的图像对比度，从而提高MRI图像的质量和对比度。造影剂可以分为T1剂，如钆（III）螯合物，其增加T1弛豫率并产生正图像对比；T2剂，如超磁性氧化铁纳米颗粒，其增加T2弛豫率并产生负图像对比。大多数临床使用的造影剂是Gd3+螯合剂，由于其高顺磁性，优异的松弛增强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造影剂增强无效的问题，因此对血管造影增强无效。此外，Gd3+的线性螯合物（如DTPA）在临床中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，因为它们具有长期循环特性，并且通过使用靶向配体具有组织选择性的潜力。这种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。不幸的是，迄今为止，大多数大分子和纳米颗粒载体都存在安全性问题，如肾脏滤过不良、肝胆摄取和生物积累。此外，它们的合成和/或自组装限制了大多数材料的球形。我们寻求开发基于可降解的、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、低毒性的水解产物。所提出的聚轮烷设计的基本假设是，其灵活的棒状形态可以通过限制巨噬细胞摄取和快速肾脏清除来极大地增强其药代动力学，同时通过适当选择末端连接和/或聚合物核来控制其清除率，从而解决下一代MRI造影剂开发中的一个主要挑战。

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.