The goal of this research project is to design and develop a new generation of biodegradable macromolecular MRI contrast agents with high kinetic chelation stability for non-invasive evaluation of the efficacy of cancer therapies. Timely and accurate assessment of cancer treatments is critical for achieving the best possible therapeutic outcomes and improving the survival of cancer patients and the quality of their lives. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) can quantitatively measure the changes of tumor physiology before any morphological changes can be observed. In this research project, we propose to design and develop polydisulfides containing macrocyclic Gd(III) chelates as a new generation of biodegradable macromolecular MRI contrast agents and to explore their applications in tumor imaging and non-invasive assessment of the efficacy of anticancer therapies. The macrocyclic Gd(III) chelates have shown high thermodynamic and kinetic chelation stability against transmetallation with endogenous ions and excrete intact from the body. The novel biodegradable macromolecular MRI contrast agents will have an improved safety profile and provide more accurate assessment of therapeutic efficacy with DCE-MRI.
The specific aims of the project are 1) to design, synthesize and characterize polydisulfides containing macrocyclic Gd(III) chelates of high kinetic chelation stability as a new generation of biodegradable macromolecular MRI contrast agents;2) to evaluate the relaxivities, degradability and kinetic chelation stability of the novel polydisulfide Gd(III) complexes;3) to investigate in vivo kinetic stability of the Gd(III) chelates, in vivo degradation, pharmacokinetics, clearance and long-term tissue accumulation of the synthesized new biodegradable macromolecular contrast agents in animal models;4) to investigate the effectiveness of the novel biodegradable macromolecular contrast agents in cancer imaging with conventional and dynamic contrast enhanced MRI and in non-invasive assessment of the therapeutic efficacy of anti-HIF-11 RNAi for cancer therapy in animal tumor models. Our long-term goal is to develop safe effective biodegradable macromolecular contrast agents with high kinetic chelation stability for accurate non-invasive assessment of the efficacy of anticancer therapies with DCE-MRI.

Public Health Relevance

Novel MRI contrast agents with an improved safety profile will be designed and developed for non- invasive assessment of the therapeutic efficacy of anticancer treatment with MRI. Timely and accurate assessment of therapeutic efficacy will have a great potential to improve therapeutic outcome and cancer treatment management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB000489-10
Application #
8235911
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Liu, Christina
Project Start
2002-12-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
10
Fiscal Year
2012
Total Cost
$346,804
Indirect Cost
$121,804
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Gujrati, Maneesh; Malamas, Anthony; Shin, Tesia et al. (2014) Multifunctional cationic lipid-based nanoparticles facilitate endosomal escape and reduction-triggered cytosolic siRNA release. Mol Pharm 11:2734-44
Jin, Erlei; Lu, Zheng-Rong (2014) Biodegradable iodinated polydisulfides as contrast agents for CT angiography. Biomaterials 35:5822-9
Mathieu, Kelsey B; Cody, Dianna D (2013) Partial arc beam filtration: a novel approach to reducing CT breast radiation dose. AJR Am J Roentgenol 200:601-7
Ye, Zhen; Wu, Xueming; Tan, Mingqian et al. (2013) Synthesis and evaluation of a polydisulfide with Gd-DOTA monoamide side chains as a biodegradable macromolecular contrast agent for MR blood pool imaging. Contrast Media Mol Imaging 8:220-8
Ye, Zhen; Jeong, Eun-Kee; Wu, Xueming et al. (2012) Polydisulfide manganese(II) complexes as non-gadolinium biodegradable macromolecular MRI contrast agents. J Magn Reson Imaging 35:737-44
Mathieu, Kelsey B; Kappadath, S Cheenu; White, R Allen et al. (2011) An empirical model of diagnostic x-ray attenuation under narrow-beam geometry. Med Phys 38:4546-55
Wu, Xueming; Zong, Yuda; Ye, Zhen et al. (2010) Stability and biodistribution of a biodegradable macromolecular MRI contrast agent Gd-DTPA cystamine copolymers (GDCC) in rats. Pharm Res 27:1390-7
Mathieu, Kelsey B; McNitt-Gray, Michael F; Zhang, Di et al. (2010) Precision of dosimetry-related measurements obtained on current multidetector computed tomography scanners. Med Phys 37:4102-9
Wu, Xueming; Jeong, Eun-Kee; Emerson, Lyska et al. (2010) Noninvasive evaluation of antiangiogenic effect in a mouse tumor model by DCE-MRI with Gd-DTPA cystamine copolymers. Mol Pharm 7:41-8
Wu, Xueming; Feng, Yi; Jeong, Eun-Kee et al. (2009) Tumor characterization with dynamic contrast enhanced magnetic resonance imaging and biodegradable macromolecular contrast agents in mice. Pharm Res 26:2202-8

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