title: A new class of macrocyclic lanthanide complexes for cell labeling and magnetic resonance imaging applications.
abstract: Lanthanide complexes have wide applications in biochemical research and biomedical imaging. We have designed and synthesized a new class of macrocyclic lanthanide chelates, Ln/DTPA-PDA-C(n), for cell labeling and magnetic resonance imaging (MRI) applications. Two lipophilic Gd3+ complexes, Gd/DTPA-PDA-C(n) (n = 10, 12), labeled a number of cultured mammalian cells noninvasively at concentrations as low as a few micromolar. Cells took up these agents rapidly and showed robust intensity increases in T1-weighed MR images. Labeled cells showed normal morphology and doubling time as control cells. In addition to cultured cells, these agents also labeled primary cells in tissues such as dissected pancreatic islets. To study the mechanism of cellular uptake, we applied the technique of diffusion enhanced fluorescence resonance energy transfer (DEFRET) to determine the cellular localization of these lipophilic lanthanide complexes. After loading cells with a luminescent complex, Tb/DTPA-PDA-C10, we observed DEFRET between the Tb3+ complex and extracellular, but not intracellular, calcein. We concluded that these cyclic lanthanide complexes label cells by inserting two hydrophobic alkyl chains into cell membranes with the hydrophilic metal binding site facing the extracellular medium. As the first imaging application of these macrocyclic lanthanide chelates, we labeled insulin secreting beta-cells with Gd/DTPA-PDA-C12. Labeled cells were encapsulated in hollow fibers and were implanted in a nude mouse. MR imaging of implanted beta-cells showed that these cells could be followed in vivo for up to two weeks. The combined advantages of this new class of macrocyclic contrast agents ensure future imaging applications to track cell movement and localization in different biological systems.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zheng
authors.forename: Houquan
authors.initials: H
authors.lastname: Dai
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Merritt
authors.forename: Craig
authors.initials: C
authors.lastname: Malloy
authors.forename: Cai Yuan
authors.initials: CY
authors.lastname: Pan
authors.forename: Wen-Hong
authors.initials: WH
authors.lastname: Li
mesh_terms: D000818:Animals; D002455:Cell Division; D002460:Cell Line; D048429:Cell Size; D003500:Cyclization; D031541:Fluorescence Resonance Energy Transfer; D005682:Gadolinium / Q000737:chemistry* / Q000145:classification; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D008163:Luminescent Measurements; D008187:Lutetium / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D013194:Staining and Labeling / Q000295:instrumentation / Q000379:methods*; D013725:Terbium / Q000737:chemistry* / Q000145:classification
chemical_list: D013725:Terbium; D008187:Lutetium; D005682:Gadolinium