Liposomal Fe(III) Macrocyclic Complexes with Hydroxypropyl Pendants as MRI Probes

Paramagnetic liposomes containing Fe(III) complexes were prepared by incorporation of mononuclear (Fe(L1) or Fe(L3)) or dinuclear (Fe₂(L2)) coordination complexes of 1,4,7-triazacyclononane macrocycles containing 2-hydroxypropyl pendant groups. Two different types of paramagnetic liposomes were prepared. The first type, LipoA, has the mononuclear Fe(L1) complex loaded into the internal aqueous core. The second type, LipoB, has the amphiphilic Fe(L3) complex inserted into the liposomal bilayer and the internal aqueous core loaded with either Fe(L1) (LipoB1) or Fe₂(L2) (LipoB2). LipoA enhances both T₁ and T₂ water proton relaxation rates. Treatment of LipoA with osmotic gradients to produce a nonspherical liposome produces a liposome with a chemical exchange saturation transfer effect as shown by an asymmetry analysis but only at high osmolarity. LipoB1, which contains an amphiphilic complex in the liposomal bilayer, produced a broadened Z-spectrum upon treatment of the liposome with osmotic gradients. The r₁ relaxivity of LipoB1 and LipoB2 were higher than the r₁ relaxivity of LipoA on a per Fe basis, suggesting an important contribution from the amphiphilic Fe(III) center. The r₁ relaxivities of paramagnetic liposomes are relatively constant over a range of magnetic field strengths (1.4-9.4 T), with the ratio of r₂/r₁ substantially increasing at high field strengths. MRI studies of LipoB1 in mice showed prolonged contrast enhancement in blood compared to the clinically employed Gd(DOTA), which was injected at a 2-fold higher dose per metal than the Fe(III)-loaded liposomes.