Conformation and structure of polymeric contrast agents for medical imaging.
The structure of Gd-DTPA-polylysine, Gd-DOTA-polylysine, Gd-SCN-Bz-DOTA-polylysine, and Gd-DTPA-poly(glu:lys) was investigated with circular dichroism, gel permeation chromatography, low angle light scattering, and proton longitudinal relaxivity. Molecular modeling calculations were performed and predicted helical secondary structure for charged Gd-chelator residues, i.e., Gd-DTPA, when the DTPA conjugation levels reached 90% and higher. This helical secondary structure was observed with circular dichroism. The conformational transition from coiled to extended linear was observed also by gel permeation chromatography and by proton relaxivity measurements. The helical secondary structure was not observed when the chelator was changed to DOTA. The residue charge interactions were eliminated in this case since the Gd-DOTA complex had no net charge. For this construct, the gel permeation and relaxivity measurements indicated a coiled conformation. An extended linear conformation was regained when the chelator complex was changed to Gd-SCN-Bz-DOTA, which had a net negative charge. The functional aspects of these structures were investigated by MR imaging of an animal tumor model. The linear extended polymer constructs gave 10-fold higher tumor signals then the coiled-collapsed constructs, indicating a much higher degree of trans-endothelial transport in the tumors.
Uzgiris
E E
EE
General Electric Global Research Center, Niskayuna, New York 12309, USA. uzgiris@crd.ge.com
Cline
Harvey
H
Moasser
Bahram
B
Grimmond
Brian
B
Amaratunga
Mohan
M
Smith
Joanne F
JF
Goddard
Gregory
G
D000818:Animals; D002614:Chelating Agents; D003287:Contrast Media / Q000737:chemistry* / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009369:Neoplasms / Q000175:diagnosis / Q000473:pathology; D004369:Pentetic Acid; D011107:Polylysine; D011108:Polymers / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017433:Protein Structure, Secondary
D002614:Chelating Agents; D003287:Contrast Media; D006573:Heterocyclic Compounds, 1-Ring; D011108:Polymers; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D011107:Polylysine; D004369:Pentetic Acid