title: Synthesis and evaluation of globular Gd-DOTA-monoamide conjugates with precisely controlled nanosizes for magnetic resonance angiography.
abstract: The purpose of this study was to design and prepare macromolecular contrast agents (CAs) with a precisely defined globular structure for MR angiography and tumor angiogenesis imaging. Generations 1 through 3 (Gd-DOTA-monoamide)-poly-L-lysine octasilsesquioxane dendrimers were prepared as nanoglobular MRI CAs. The nanoglobular Gd(III) chelates had a well-defined compact globular structure and high loading of Gd-DOTA-monoamide at their surface. The size of the G1, G2, and G3 nanoglobular MRI CAs was approximately 2.0, 2.4, and 3.2 nm, respectively. The T1 relaxivity of G1, G2, and G3 nanoglobular MRI CAs was approximately 6.4, 7.2, and 10.0 mM(-1) sec(-1) at 3T, respectively. The nanoglobular MRI CAs showed size-dependent contrast enhancement within the mouse vasculature, which gradually decayed to baseline after a 60 min session. The G3 nanoglobular CA resulted in more significant and prolonged vascular enhancement than the smaller nanoglobular agents at 0.03 mmol Gd/kg. The G3 agent also provided significant and prolonged contrast enhancement in the heart and vasculature at a dose as low as 0.01 mmol Gd/kg, 1/10th of the regular clinical dose. Significant enhancement was observed in tumor for all CAs. The nanoglobular CAs cleared via renal filtration and accumulated in the urinary bladder as shown in the dynamic MR images. The nanoglobular Gd(III) chelates are effective intravascular MRI CAs at substantially reduced doses. The nanoglobular MRI CAs are promising for further preclinical development for MR angiography and MR imaging of tumor angiogenesis.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84108, USA.
authors.forename: Todd Lyle
authors.initials: TL
authors.lastname: Kaneshiro
authors.forename: Eun-Kee
authors.initials: EK
authors.lastname: Jeong
authors.forename: Glen
authors.initials: G
authors.lastname: Morrell
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Parker
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D003287:Contrast Media / Q000737:chemistry*; D005260:Female; D005682:Gadolinium / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry*; D018810:Magnetic Resonance Angiography / Q000295:instrumentation* / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D008968:Molecular Conformation; D053758:Nanoparticles / Q000737:chemistry; D009369:Neoplasms / Q000473:pathology; D009389:Neovascularization, Pathologic; D009942:Organometallic Compounds / Q000737:chemistry*
chemical_list: D000577:Amides; D002614:Chelating Agents; D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D005682:Gadolinium
references.citation: Invest Radiol. 1991 Nov;26(11):969-74
references.pmid: 1743920
references.citation: Mol Pharm. 2005 Jul-Aug;2(4):302-11
references.pmid: 16053333
references.citation: Phys Med. 2007 Dec;23(3-4):85-90
references.pmid: 18061121
references.citation: Bioconjug Chem. 2003 Mar-Apr;14(2):388-94
references.pmid: 12643749
references.citation: Pharm Res. 2006 Aug;23(8):1736-42
references.pmid: 16850267
references.citation: Am J Physiol Renal Physiol. 2006 Nov;291(5):F1083-9
references.pmid: 16735459
references.citation: Mol Pharm. 2007 Sep-Oct;4(5):759-68
references.pmid: 17705440
references.citation: Magn Reson Med. 2001 Dec;46(6):1169-73
references.pmid: 11746584
references.citation: Bioconjug Chem. 2001 Jan-Feb;12(1):100-7
references.pmid: 11170372
references.citation: Radiology. 2007 Apr;243(1):148-57
references.pmid: 17267695
references.citation: Kidney Int. 2007 Aug;72(3):260-4
references.pmid: 17507905
references.citation: Pharm Res. 2007 Jun;24(6):1208-16
references.pmid: 17387601
references.citation: Magn Reson Med. 2001 Mar;45(3):454-60
references.pmid: 11241704
references.citation: NMR Biomed. 2006 Feb;19(1):133-41
references.pmid: 16450331
references.citation: Bioconjug Chem. 1999 May-Jun;10(3):361-70
references.pmid: 10346865
references.citation: Biomacromolecules. 2007 May;8(5):1519-29
references.pmid: 17402781
references.citation: Bioconjug Chem. 2006 Jul-Aug;17(4):975-87
references.pmid: 16848405
references.citation: J Magn Reson Imaging. 1997 Nov-Dec;7(6):963-71
references.pmid: 9400838
references.citation: Bioconjug Chem. 2004 Nov-Dec;15(6):1424-30
references.pmid: 15546211
references.citation: Exp Biol Med (Maywood). 2007 Sep;232(8):1081-9
references.pmid: 17720954
references.citation: Radiology. 2007 Apr;243(1):105-11
references.pmid: 17329684
references.citation: Pharm Sci Technol Today. 1999 Nov;2(11):441-449
references.pmid: 10542390
references.citation: Biomacromolecules. 2003 Mar-Apr;4(2):249-58
references.pmid: 12625719
references.citation: J Interv Cardiol. 2003 Dec;16(6):457-63
references.pmid: 14632941
references.citation: Magn Reson Med. 2001 Oct;46(4):795-802
references.pmid: 11590657
references.citation: Eur J Pharm Sci. 1999 Feb;7(3):243-8
references.pmid: 9845812
references.citation: Chemistry. 2005 May 6;11(10):3064-76
references.pmid: 15776490
references.citation: Hemodial Int. 2007 Oct;11 Suppl 3:S2-6
references.pmid: 17897106
references.citation: Int J Nanomedicine. 2006;1(1):31-40
references.pmid: 17722260