title: Gadolinium MRI contrast agents based on triazine dendrimers: relaxivity and in vivo pharmacokinetics.
abstract: Four gadolinium (Gd)-based macromolecular contrast agents, G3-(Gd-DOTA)(24), G5-(Gd-DOTA)(96), G3-(Gd-DTPA)(24), and G5-(Gd-DTPA)(96), were prepared that varied in the size of dendrimer (generation three and five), the type of chelate group (DTPA or DOTA), and the theoretical number of metalated chelates (24 and 96). Synthesis relied on a dichlorotriazine derivatized with a DOTA or DTPA ligand that was incorporated into the dendrimer and ultimately metalated with Gd ions. Paramagnetic characteristics and in vivo pharmacokinetics of all four contrast agents were investigated. The DOTA-containing agents, G3-(Gd-DOTA)(24) and G5-(Gd-DOTA)(96), demonstrated exceptionally high r1 relaxivity values at off-peak magnetic fields. Additionally, G5-(Gd-DOTA)(96) showed increased r1 relaxivity in serum compared to that in PBS, which was consistent with in vivo images. While G3-(Gd-DOTA)(24) and G3-(Gd-DTPA)(24) were rapidly excreted into the urine, G5-(Gd-DOTA)(96) and G5-(Gd-DTPA)(96) did not clear as quickly through the kidneys. Molecular simulation of the DOTA-containing dendrimers suggests that a majority of the metalated ligands are accessible to water. These triazine dendrimer-based MRI contrast agents exhibit several promising features such as high in vivo r1 relaxivity, desirable pharmacokinetics, and well-defined structure.
authors.affiliation: Department of Chemistry, Texas Christian University, Fort Worth, TX 76129, USA.
authors.forename: Jongdoo
authors.initials: J
authors.lastname: Lim
authors.forename: Baris
authors.initials: B
authors.lastname: Turkbey
authors.forename: Marcelino
authors.initials: M
authors.lastname: Bernardo
authors.forename: L Henry
authors.initials: LH
authors.lastname: Bryant
authors.forename: Matteo
authors.initials: M
authors.lastname: Garzoni
authors.forename: Giovanni M
authors.initials: GM
authors.lastname: Pavan
authors.forename: Takahito
authors.initials: T
authors.lastname: Nakajima
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
authors.forename: Eric E
authors.initials: EE
authors.lastname: Simanek
authors.forename: Hisataka
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D005682:Gadolinium / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014227:Triazines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D003287:Contrast Media; D050091:Dendrimers; D009942:Organometallic Compounds; D014227:Triazines; D005682:Gadolinium