Cancer remains one of the leading causes of death in the industrialized world. Modern imaging technologies employ contrast agents to visualize tumor anatomy and physiology, which can provide information on malignancy and the response to treatment. Currently, all useful MRI contrast agents require some kind of chemical labeling, i.e. with paramagnetic metals or, recently, with hyperpolarized magnetic isotopes. We here propose the development of simple D-glucose as an MRI contrast agent. We will accomplish this by using the hydroxyl protons on glucose as a natural magnetic label that can be activated using specially designed series of radiofrequency (RF) pulses. This label is transferred to water and can be detected using standard MRI hardware. Some of the advantages of using a natural agent such as D-glucose at an appropriate dose are safety, absence of interference with contrast on standard anatomical images, low cost, and the ability to perform repeated studies over a short period of time. Our hypothesis is that D-glucose can be used as an infusible MRI contrast agent that provides information on two important aspects of tumor physiology, namely perfusion and permeability. We foresee that translation to clinical application will be fast since D-glucose is already widely used for other indications, such as the glucose tolerance test for diabetes, and its safety profile is well established. We have recently acquired initial data showing the MRI detectability of D-glucose at millimolar concentrations in phantoms, in animal models and in a first brain tumor patient. Our overall goal is to develop and translate to the clinc the use of D-glucose as an infusible MRI contrast agent for the combined imaging of tumor perfusion and permeability. We therefore have established engineering, biochemical and clinical aims to (i) design and optimize the MRI pulse sequence technology needed to detect D-glucose through the water signal in phantoms and animals, (ii) to translate the MRI pulse sequence methodology to human scanners, (iii) to design data analysis approaches and software packages for visualizing tumor enhancement and obtaining physiological indicators of tumor perfusion and permeability, (iv) investigate the mechanism of contrast, (v) To demonstrate the suitability of D-glucose as an MRI contrast agent for brain tumor patients first at 7T and subsequently 3T, and (vi) To optimize and standardize a clinical MRI protocol for reproducible intravenous D- glucose imaging In order to accomplish this with optimal efficiency and proper validation and to assure clinical relevance, we propose a Bioengineering Research Partnership of experts in the fields of MRI pulse sequence development, cancer biology, clinical oncology, biostatistics, and endocrinology, which will employ the facilities of several Resource Centers available at the Hugo Moser Research Institute at Kennedy Krieger and Johns Hopkins University.

Public Health Relevance

Annually, about 8,500,000 patients people worldwide are injected with a synthetic gadolinium imaging contrast agent for MRI. While these agents are extremely safe, they have the potential for adverse effects in some patient populations, which may accumulate when a procedure is repeated. We propose to develop the use of sugar (D-glucose) as a biodegradable contrast agent for imaging tumor physiology with MRI. We will first develop and translate this approach for brain cancer, after which the technology can be adjusted for use in other cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB019934-03
Application #
9210625
Study Section
Special Emphasis Panel (ZRG1-SBIB-Z (55)R)
Program Officer
Liu, Guoying
Project Start
2015-05-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$1,038,553
Indirect Cost
$367,274
Name
Hugo W. Moser Research Institute Kennedy Krieger
Department
Type
Research Institutes
DUNS #
155342439
City
Baltimore
State
MD
Country
United States
Zip Code
21205