title: Synthesis and characterization of poly(L-glutamic acid) gadolinium chelate: a new biodegradable MRI contrast agent.
abstract: Most currently evaluated macromolecular contrast agents for magnetic resonance imaging (MRI) are not biodegradable. The goal of this study is to synthesize and characterize poly(l-glutamic acid) (PG) gadolinium chelates as biodegradable blood-pool MRI contrast agents. Two PG chelates of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) were synthesized through the use of difunctional and monofunctional DTPA precursors. The conjugates were characterized with regard to molecular weight and molecular weight distribution, gadolinium content, relaxivity, and degradability. Distributions of the polymeric MRI contrast agents in various organs were determined by intravenous injection of (111)In-labeled polymers into mice bearing murine breast tumors. MRI scans were performed at 1.5 T in mice after bolus injection of the polymeric chelates. PG-Hex-DTPA-Gd, obtained from aminohexyl-substituted PG and DTPA-dianhydride, was partially cross-linked and was undegradable in the presence of cathepsin B. On the other hand, PG-Bz-DTPA-Gd synthesized directly from PG and monofunctional p-aminobenzyl-DTPA(acetic acid-tert-butyl ester) was a linear polymer and was degradable. The relaxivities of the polymers at 1.5 T were 3-8 times as great as that of Gd-DTPA. Both polymers had high blood concentrations and were primarily accumulated in the kidney. However, PG-Bz-DTPA-Gd was gradually cleared from the body and had significantly less retention in the blood, the spleen, and the kidney. MRI with PG-Bz-DTPA-Gd in mice showed enhanced vascular contrast at up to 2 h after the contrast agent injection. The ability of PG-Bz-DTPA-Gd to be degraded and cleared from the body makes it a favorable macromolecular MRI contrast agent.
authors.affiliation: Department of Experimental Diagnostic Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Wen
authors.forename: Edward F
authors.initials: EF
authors.lastname: Jackson
authors.forename: Roger E
authors.initials: RE
authors.lastname: Price
authors.forename: E Edmund
authors.initials: EE
authors.lastname: Kim
authors.forename: Qingping
authors.initials: Q
authors.lastname: Wu
authors.forename: Sidney
authors.initials: S
authors.lastname: Wallace
authors.forename: Chusilp
authors.initials: C
authors.lastname: Charnsangavej
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.forename: Chun
authors.initials: C
authors.lastname: Li
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000138:chemical synthesis* / Q000378:metabolism; D003287:Contrast Media / Q000138:chemical synthesis* / Q000378:metabolism; D005260:Female; D005682:Gadolinium / Q000737:chemistry* / Q000378:metabolism; D018698:Glutamic Acid / Q000138:chemical synthesis* / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008809:Mice, Inbred C3H
chemical_list: D002614:Chelating Agents; D003287:Contrast Media; D018698:Glutamic Acid; D005682:Gadolinium