title: Method for enhancing cell penetration of Gd3+-based MRI contrast agents by conjugation with hydrophobic fluorescent dyes.
abstract: Gadolinium ion (Gd(3+)) complexes are commonly used as magnetic resonance imaging (MRI) contrast agents to enhance signals in T(1)-weighted MR images. Recently, several methods to achieve cell-permeation of Gd(3+) complexes have been reported, but more general and efficient methodology is needed. In this report, we describe a novel method to achieve cell permeation of Gd(3+) complexes by using hydrophobic fluorescent dyes as a cell-permeability-enhancing unit. We synthesized Gd(3+) complexes conjugated with boron dipyrromethene (BDP-Gd) and Cy7 dye (Cy7-Gd), and showed that these conjugates can be introduced efficiently into cells. To examine the relationship between cell permeability and dye structure, we further synthesized a series of Cy7-Gd derivatives. On the basis of MR imaging, flow cytometry, and ICP-MS analysis of cells loaded with Cy7-Gd derivatives, highly hydrophobic and nonanionic dyes were effective for enhancing cell permeation of Gd(3+) complexes. Furthermore, the behavior of these Cy7-Gd derivatives was examined in mice. Thus, conjugation of hydrophobic fluorescent dyes appears to be an effective approach to improve the cell permeability of Gd(3+) complexes, and should be applicable for further development of Gd(3+)-based MRI contrast agents.
authors: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan.
authors: Takehiro
authors: T
authors: Yamane
authors: Kenjiro
authors: K
authors: Hanaoka
authors: Yasuaki
authors: Y
authors: Muramatsu
authors: Keita
authors: K
authors: Tamura
authors: Yusuke
authors: Y
authors: Adachi
authors: Yasushi
authors: Y
authors: Miyashita
authors: Yasunobu
authors: Y
authors: Hirata
authors: Tetsuo
authors: T
authors: Nagano
mesh_terms: D000818:Animals; D002232:Carbocyanines / Q000737:chemistry* / Q000378:metabolism*; D003287:Contrast Media / Q000737:chemistry* / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D005682:Gadolinium / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D041681:NIH 3T3 Cells
chemical_list: D002232:Carbocyanines; D003287:Contrast Media; D005456:Fluorescent Dyes; C501744:indotricarbocyanine; D005682:Gadolinium