UVM Theses and Dissertations
Format:
Print
Author:
Duncan, Alexandra K.
Dept./Program:
Chemistry
Year:
2013
Degree:
MS
Abstract:
Many of the clinically available MRI contrast agents are based on comflexes of Gd³ ions with a polyaminocarboxylate scaffold, such as- [Gd(DTPA)(H₂O)]⁻² (dtpa = diethylenetriamine pentaacetic acid). Porous particles are attractive substrates for the immobilization of MRI contrast agents, because the particles can be modified with biomolecules to target specific tissues in vivo, leading to new applications in therapy and multimodal imaging. Moreover, particle-based MRI contrast agents have proven to be more sensitive, due to decreased molecular tumbling rates, and per-particle relaxivities can be quite large due to the large number of complexes that can be immobilized.
Studies have demonstrated that structurally complex polydentate ligands have not exhibited superior performance in the uptake of lanthanide ions as compared to novel phosphonate chelators. A ligand with a phosphonate backbone should allow for a fast water exchange rate to be retained, and favor the formation of stronger hydrogen bonds (compared to carboxylates), keeping water molecules closer to the coordination sphere of the complex. We hypothesize that by immobilizing a phosphonate-based ligand (imido diphosphonate, "NDP₂") onto nanoporous silica microparticles, we could fine-tune relaxivity values of these materials. To test this hypothesis we synthesized silica microparticles with three different pore sizes and modified them with NDP₂ complex.
We found that the r₁ and r₂ relaxivity parameters were significantly higher than for [Gd(DTPA)(H₂O)]⁻² or the related complex, [Gd(DOTA)(H₂O)]⁻; in some cases, we measured a 3 to 5- fold increase in these parameters relative to the free Gd complexes. Per-particle relaxivities were on the order of 10⁷ mM⁻¹s⁻¹. These data indicated that Gd-phosphonate complexes are particularly promising in particle-based MRI techniques. We describe our efforts toward the synthesis of a free ligand with an architecture similar to that of the proposed structure of NDP₂ to understand the metal coordination environment of the Gd-NDP₂ complex on the particles. Three different synthetic routes were employed in an attempt to synthesize a phosphonate-based ligand. While these sutdies did not result in the synthesis of the desired ligand, the results led us to propose a new structure on the surface of the particles.
Studies have demonstrated that structurally complex polydentate ligands have not exhibited superior performance in the uptake of lanthanide ions as compared to novel phosphonate chelators. A ligand with a phosphonate backbone should allow for a fast water exchange rate to be retained, and favor the formation of stronger hydrogen bonds (compared to carboxylates), keeping water molecules closer to the coordination sphere of the complex. We hypothesize that by immobilizing a phosphonate-based ligand (imido diphosphonate, "NDP₂") onto nanoporous silica microparticles, we could fine-tune relaxivity values of these materials. To test this hypothesis we synthesized silica microparticles with three different pore sizes and modified them with NDP₂ complex.
We found that the r₁ and r₂ relaxivity parameters were significantly higher than for [Gd(DTPA)(H₂O)]⁻² or the related complex, [Gd(DOTA)(H₂O)]⁻; in some cases, we measured a 3 to 5- fold increase in these parameters relative to the free Gd complexes. Per-particle relaxivities were on the order of 10⁷ mM⁻¹s⁻¹. These data indicated that Gd-phosphonate complexes are particularly promising in particle-based MRI techniques. We describe our efforts toward the synthesis of a free ligand with an architecture similar to that of the proposed structure of NDP₂ to understand the metal coordination environment of the Gd-NDP₂ complex on the particles. Three different synthetic routes were employed in an attempt to synthesize a phosphonate-based ligand. While these sutdies did not result in the synthesis of the desired ligand, the results led us to propose a new structure on the surface of the particles.