The main aim of this research is to develop biodegradable macromolecular gadolinium (III) complexes as safe, effective MRI contrast agents for cancer imaging. Macromolecular agents have a prolonged plasma and tissue retention time and can preferentially accumulate in solid tumors because of the vascularity of malignant tumors and the hyperpermeability of tumor blood vessels. It has been demonstrated in the last decade that macromolecular contrast agents are superior in cancer detection and staging and neoplastic angiogenesis imaging to the low molecular weight MRI contrast agents used in clinics, and may have a potential for noninvasive imaging of cancer treatment response with MRI. However, the slow metal clearance and consequent toxic effects have limited the clinical development of macromolecular Gd(III) complexes. Innovative approaches are required to solve this problem. We intend to develop a new class of biodegradable macromolecular Gd(III) complexes, which can be degraded into smaller molecules by the biomolecules in the body, which can be readily cleared from the body after the MRI exams. Biodegradable structures will be designed and incorporated into the polymer backbones of macromolecular paramagnetic complexes. The structures can be cleaved by the biomolecules in the plasma, resulting in breakage of the macromolecules into smaller complexes that can be removed through renal glomerular filtration. This project includes feasibility (R21) and development (R33) phases. In the R21 phase, biodegradable macromolecular Gd(III) complexes will be designed and synthesized to demonstrate the feasibility of the novel agents. The physicochemical and biological properties including relaxivity, degradability, acute toxicity, in vivo clearance and contrast enhancement of the agents will be preliminarily evaluated. In the R33 phase, the structures of the agents will be optimized. Their NMRD profile, safety, in vivo clearance and contrast enhancement in cancer imaging will be evaluated in detail using in vitro and in vivo methods. A lead agent with low toxicity, appropriate in vivo retention time, acceptable in vivo clearance rate and effective contrast enhancement on cancer MR imaging will be selected for further preclinical and clinical development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
4R33CA095873-02
Application #
6902055
Study Section
Special Emphasis Panel (ZCA1-SRRB-9 (J2))
Program Officer
Liu, Guoying
Project Start
2003-06-01
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
2
Fiscal Year
2004
Total Cost
$305,477
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Xu, Rongzuo; Kaneshiro, Todd Lyle; Jeong, Eun-Kee et al. (2010) Synthesis and evaluation of nanoglobule-cystamine-(Gd-DO3A), a biodegradable nanosized magnetic resonance contrast agent for dynamic contrast-enhanced magnetic resonance urography. Int J Nanomedicine 5:707-13
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
Tan, Mingqian; Wu, Xueming; Jeong, Eun-Kee et al. (2010) Peptide-targeted Nanoglobular Gd-DOTA monoamide conjugates for magnetic resonance cancer molecular imaging. Biomacromolecules 11:754-61
Tan, Mingqian; Wu, Xueming; Jeong, Eun-Kee et al. (2010) An effective targeted nanoglobular manganese(II) chelate conjugate for magnetic resonance molecular imaging of tumor extracellular matrix. Mol Pharm 7:936-43
Lu, Zheng-Rong; Wu, Xueming (2010) Polydisulfide Based Biodegradable Macromolecular Magnetic Resonance Imaging Contrast Agents. Isr J Chem 50:220-232
Liu, Xin; Feng, Yi; Lu, Zheng-Rong et al. (2010) Rapid simultaneous acquisition of T1 and T2 mapping images using multishot double spin-echo EPI and automated variations of TR and TE (ms-DSEPI-T12). NMR Biomed 23:97-104
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
Feng, Yi; Emerson, Lyska; Jeong, Eun-Kee et al. (2009) Application of a biodegradable macromolecular contrast agent in dynamic contrast-enhanced MRI for assessing the efficacy of indocyanine green-enhanced photothermal cancer therapy. J Magn Reson Imaging 30:401-6
Zong, Yuda; Wang, Xuli; Jeong, Eun-Kee et al. (2009) Structural effect on degradability and in vivo contrast enhancement of polydisulfide Gd(III) complexes as biodegradable macromolecular MRI contrast agents. Magn Reson Imaging 27:503-11

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