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

• Published in: ACS applied bio materials 2021-11, Vol.4 (11), p.7951-7960
• Main Authors: Abozeid, Samira M, Chowdhury, Md Saiful I, Asik, Didar, Spernyak, Joseph A, Morrow, Janet R
• Format: Article
• Language: English
• Subjects: Animals; Contrast Media - chemistry; Coordination Complexes - chemistry; Ferric Compounds - chemistry; Liposomes; Magnetic Resonance Imaging; Mice; Water - chemistry
• ISSN: 2576-6422; 2576-6422
• DOI: 10.1021/acsabm.1c00879

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 r 1 relaxivity of LipoB1 and LipoB2 were higher than the r 1 relaxivity of LipoA on a per Fe basis, suggesting an important contribution from the amphiphilic Fe­(III) center. The r 1 relaxivities of paramagnetic liposomes are relatively constant over a range of magnetic field strengths (1.4–9.4 T), with the ratio of r 2/r 1 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.