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

描述(申请人提供)：磁共振成像(MRI)是一种强大的工具，用于对人体内的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。磁共振成像具有无电离辐射、高对比度、高空间分辨率和良好的深度剖析能力等优点。通过使用MRI造影剂，通过改变周围水质子的纵向(T1)和横向(T2)弛豫速率，增强感兴趣组织内的图像对比度，可以改善MRI图像的质量和对比度。造影剂可分为两类：T1类试剂，如Gd(III)螯合物，可提高T1弛豫速率并产生正图像对比度；T2试剂，如超磁性氧化铁纳米颗粒，可提高T2弛豫速率并产生负图像对比度。大多数临床使用的造影剂是Gd3+螯合物，由于其高度的顺磁性、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会快速从体内清除，对比剂增强效果不佳，因此对血管造影剂增强无效。此外，Gd3+的线性络合物(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很有吸引力的，因为它们具有长循环的性质，并且可能通过使用靶向配体来实现组织选择性。这样的纳米颗粒不仅有更好的药代动力学，它们还可能携带更高的Gd3+负载量。不幸的是，到目前为止，大多数大分子和纳米颗粒载体都存在安全性问题，如肾滤过差、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的柔性棒状聚轮烷(PR)支架的长循环多价Gd3+MRI造影剂，这种支架可产生快速排泄的低毒水解物。建议的聚轮烷设计的基本假设是，它们灵活的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帽连接和/或聚合物核心来控制其清除率，从而解决下一代磁共振造影剂开发中的主要挑战。

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.