Chelating phytanyl-EDTA amphiphiles: self-assembly and promise as contrast agents for medical imaging

Abstract

Chelating amphiphiles of ethylene diamine tetraacetic acid (EDTA) have been synthesized by conjugation to one or two C20 isoprenoid-type chain/s (phytanyl) via an ester bond. EDTA-mono and bis phytanyl (EDTA-MP and EDTA-BP) have the ability to sequester a variety of metal ions, including transition metal ions and paramagnetic metal ions such as manganese (Mn) and gadolinium (Gd). Both amphiphiles and their metal complexes were examined for ordered self-assembled structures in the solid state and as hydrated lyotropic liquid crystalline phases. For the neat materials small and wide angle X-ray scattering (SAXS/WAXS) revealed lamellar structures with molten hydrophobic chains for the mono-phytanyl conjugate, however, neither Gd-EDTA-MP nor Mn-EDTA-MP showed any ordered phases. The bis-phytanyl conjugate displayed a less ordered structure, while its Mn complexed conjugate demonstrated an ordered lamellar phase with molten chains. Lyotropic liquid crystalline structures of these amphiphiles were examined by cross polarizing optical microscopy (POM) and SAXS methods in the presence of water or sodium acetate solution (100 mM, 200 mM, 500 mM and 1 M). EDTA-MP formed a lamellar liquid crystal (L_α), whilst higher order inverse hexagonal (H_II) and micellar cubic phases (I_II) with Fd3m symmetry were displayed by the bis- conjugate. Dispersions of these amphiphiles buffered in sodium acetate solution yielded submicron sized particles with analogous nanostructures (liposomes, hexosomes), which were examined by Synchrotron SAXS and visualized with Cryo-TEM. The influence of pH upon the morphology of the nanostructures was critical, with hexosomes of EDTA-BP (pH = 5.7) converting to liposomes at pH > 6. Dispersed Mn and Gd complexed particles were examined as contrast agents (CAs) for magnetic resonance imaging by low field NMR measurements. Mn and Gd complexed nanostructured particles displayed improved relaxivity over Mn-EDTA and Gd-EDTA, respectively. The formation of highly ordered nanostructured self-assembly materials by these chelating amphiphiles combined with their ability to sequester a variety of metal ions, including paramagnetic metal ions, suggests their potential application as contrast agents for MRI.