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.

Public Health Relevance

Magnetic resonance imaging (MRI) is a powerful tool for high-resolution three-dimensional medical imaging of anatomical structures and specific organs within the body. The quality of the images can be improved by the use of MR contrast agents, but unfortunately, many of the currently used agents suffer from rapid clearance, toxicity and/or bioaccumulation issues. This proposal describes the development of degradable MR contrast agents that are designed to avoid these limitations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21EB017921-01A1
Application #
8824207
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Liu, Christina
Project Start
2014-09-29
Project End
2016-07-31
Budget Start
2014-09-29
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$203,483
Indirect Cost
$50,801
Name
Purdue University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907