Synthesis and evaluation of globular Gd-DOTA-monoamide conjugates with precisely controlled nanosizes for magnetic resonance angiography.
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.
Kaneshiro
Todd Lyle
TL
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84108, USA.
Jeong
Eun-Kee
EK
Morrell
Glen
G
Parker
Dennis L
DL
Lu
Zheng-Rong
ZR
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*
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
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