Magnetic resonance imaging (MRI) is currently being researched for the diagnosis of cardiovascular disease, the leading cause of death in the US. Due to the limitations of small molecule agents, macromolecular contrast agents show promise for enhancing cardiovascular imaging. Macromolecule Gd3+ chelates have been shown to improve relativity, limits transcapillary diffusion, and increase in vivo circulation times. The long-range goal of this project is to develop a novel series of polymeric-Gd3+ chelates for use as cardiovascular MRI contrast agents. The objective of this application is to synthesize a series of fourteen polymers (seven structures at two degrees of polymerization) that contain alternating Gd3+ chelates with either a carbohydrate or non-hydroxylated spacer along the backbone. These polymers will be statistically analyzed to determine how the identity of the spacer moiety and polymer degree of polymerization affects the T1-weighted water proton relativity (r1) and cytotoxicity with a rat myocardial cell line (H9c2 2-1 cells). These goals will be accomplished by pursuing three specific aims:
Aim #1) to synthesize a novel series of glycopolymers containing gadolinium chelates that range in chemical and structural properties such as the number and stereochemistry of the hydroxyl units, the spacing of the Gd3+ chelates, and the molecular weight. The polymers will be prepared through polycondensation polymerization of diethylenetriamine pentaacetic acid-bisanhydride (DTPA-BA) with various carbohydrate monomers including L-tartaramide, D- mannaramide, D-glucaramide, and meso-galactaramide (G). Non-hydroxylated, but structurally-related model polymers with repeat units containing oxalamide, succinamide, and adipamide (in place of the carbohydrates), will also be synthesized. All materials will be constructed at two degrees of polymerization to properly assess the role of the chemical and structural characteristics on water proton relaxivity and toxicity.
Aim #2) to measure water proton relaxivity values (r1) for each of the polymers and the control, Magnevist, and statistically correlate the chemical and structural properties to the observed relaxivity values. 1 H nuclear magnetic resonance spectroscopy using an inversion recovery pulse sequence will be performed on aqueous solutions of each polymer contrast agent to determine the r1 values. The statistical correlation of the relaxivity results (via an ANOVA model) to the i) number of hydroxyl groups (0, 2, 4), ii) the hydroxyl stereochemistry (glucaramide, galactaramide, or mannaramide), iii) the chelate spacing (0, 2, or 4 methylenes), and iv) the degree of polymerization (n ~ 15 or 30) will allow the development of structure- activity relationships.
Aim #3) To measure the cytotoxicity of the polymeric contrast agents and the control, Magnevist, with the myocardial cell line and statistically correlate the chemical and structural properties to the observed toxicity values. The IC50 values will be determined by performing MTT assays and will be statistically correlated to the chemical properties in the same manner as detailed in Aim #2. Magnetic resonance imaging (MRI) is currently being researched for the diagnosis of cardiovascular disease, the leading cause of death in the US. The goal of this project is to develop and evaluate a novel series of glycopolymer-Gd3+ chelates for use as MRI contrast agents to improve cardiovascular MRI for early and accurate detection of acute myocardial afflictions. ? ? ?
| Tranter, Michael; Liu, Yemin; He, Suiwen et al. (2012) In vivo delivery of nucleic acids via glycopolymer vehicles affords therapeutic infarct size reduction in vivo. Mol Ther 20:601-8 |
| Bryson, Joshua M; Chu, Wen-Jang; Lee, Jing-Huei et al. (2008) A beta-cyclodextrin ""click cluster"" decorated with seven paramagnetic chelates containing two water exchange sites. Bioconjug Chem 19:1505-9 |
| Lucas, Robie L; Benjamin, Michael; Reineke, Theresa M (2008) Comparison of a tartaric acid derived polymeric MRI contrast agent to a small molecule model chelate. Bioconjug Chem 19:24-7 |
