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 #
5R01EB000489-12
Application #
8610917
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Liu, Christina
Project Start
2002-12-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
12
Fiscal Year
2014
Total Cost
$336,274
Indirect Cost
$118,024
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ye, Zhen; Zhou, Zhuxian; Ayat, Nadia et al. (2016) A neutral polydisulfide containing Gd(III) DOTA monoamide as a redox-sensitive biodegradable macromolecular MRI contrast agent. Contrast Media Mol Imaging 11:32-40
Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong (2016) A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging. Biomaterials 85:168-79
Gujrati, Maneesh; Vaidya, Amita; Lu, Zheng-Rong (2016) Multifunctional pH-Sensitive Amino Lipids for siRNA Delivery. Bioconjug Chem 27:19-35
Zhou, Zhuxian; Mondjinou, Yawo; Hyun, Seok-Hee et al. (2015) Gd3+-1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic-2-hydroxypropyl-β-cyclodextrin/Pluronic Polyrotaxane as a Long Circulating High Relaxivity MRI Contrast Agent. ACS Appl Mater Interfaces 7:22272-6
Parvani, Jenny G; Gujrati, Maneesh D; Mack, Margaret A et al. (2015) Silencing β3 Integrin by Targeted ECO/siRNA Nanoparticles Inhibits EMT and Metastasis of Triple-Negative Breast Cancer. Cancer Res 75:2316-25
Zhou, Zhuxian; Qutaish, Mohammed; Han, Zheng et al. (2015) MRI detection of breast cancer micrometastases with a fibronectin-targeting contrast agent. Nat Commun 6:7984
Han, Zheng; Zhou, Zhuxian; Shi, Xiaoyue et al. (2015) EDB Fibronectin Specific Peptide for Prostate Cancer Targeting. Bioconjug Chem 26:830-8
Malamas, Anthony S; Jin, Erlei; Zhang, Qi et al. (2015) Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model. Pharm Res 32:3029-43
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

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