High-stability spherical lanthanide nanoclusters for magnetic resonance imaging

Abstract

High-nuclear lanthanide clusters have shown great potential for the administration of high-dose mononuclear gadolinium chelates in magnetic resonance imaging (MRI). The development of high-nuclear lanthanide clusters with excellent solubility and high stability in water or solution has been challenging and is very important for expanding the performance of MRI. We used N-methylbenzimidazole-2-methanol (HL) and LnCl₃·6H₂O to synthesize two spherical lanthanide clusters, Ln₃₂ (Ln = Ho, Ho₃₂; and Ln = Gd, Gd₃₂), which are highly stable in solution. The 24 ligands L^- are all distributed on the periphery of Ln₃₂ and tightly wrap the cluster core, ensuring that the cluster is stable. Notably, Ho₃₂ can remain highly stable when bombarded with different ion source energies in HRESI-MS or immersed in an aqueous solution of different pH values for 24 h. The possible formation mechanism of Ho₃₂ was proposed to be Ho(III), (L)^- and H₂O → Ho₃(L)₃/Ho₃(L)₄ → Ho₄(L)₄/Ho₄(L)₅ → Ho₆(L)₆/Ho₆(L)₇ → Ho₁₆(L)₁₉ → Ho₂₈(L)₁₅ → Ho₃₂(L)₂₄/Ho₃₂(L)₂₁/Ho₃₂(L)₂₃. To the best of our knowledge, this is the first study of the assembly mechanism of spherical high-nuclear lanthanide clusters. Spherical cluster Gd₃₂, a form of highly aggregated Gd(III), exhibits a high longitudinal relaxation rate (1 T, r₁ = 265.87 mM^-1·s^-1). More notably, compared with the clinically used commercial material Gd-DTPA, Gd₃₂ has a clearer and higher-contrast T₁-weighted MRI effect in mice bearing 4T1 tumors. This is the first time that high-nuclear lanthanide clusters with high water stability have been utilized for MRI. High-nuclear Gd clusters containing highly aggregated Gd(III) at the molecular level have higher imaging contrast than traditional Gd chelates; thus, using large doses of traditional gadolinium contrast agents can be avoided.

Keywords: T1-weighted MRI; assembly mechanism; high stability; lanthanide clusters; low toxicity.

Scheme 1.

Spherical nanocluster Gd₃₂ acts as a T₁-weighted MRI CA for the diagnosis of tumors.

Figure 1.

Molecular structure (a), core structure (b) and metal connection (c) of Ho₃₂ (free Cl⁻ ions and solvent molecules have been omitted for clarity). (d) Space-filling mode of Ho₃₂, in which all ligands protected the cluster core. (e) Simplified molecular structure diagram of Ho₃₂, which contains Ho(III) ions in two different coordination environments.

Figure 2.

(a) HRESI-MS spectra of Ho₃₂ in DMF at different ion source voltages (in-source CID). (b) Comparison of the PXRD observation value and its simulated value after Ho₃₂ was immersed in solutions of different pH values for 24 h. (c) The ligands formed a protective layer through hydrogen bonding to prevent H₂O from attacking the cluster core (the dotted line represents the hydrogen bond).

Figure 3.

(a) Time-dependent HRESI-MS tracking the formation of Ho₃₂. (b) HRESI-MS spectra intensity-time profiles of the species. (c) The possible Ho₃₂ assembly mechanism.

Figure 4.

(a) The r₁ and r₂ relaxivities of Gd₃₂ and Gd-DTPA solutions containing the same Gd(III) ion concentrations at 1 T and 3 T magnetic fields. Corresponding T₁-weighted MR imaging of Gd(III) ions (Gd₃₂ and Gd-DTPA) at 1 T (b) and 3 T (c). T₁-weighted MR imaging of Gd(III) ions (Gd₃₂ and Gd-DTPA) incubated with 4T1 cells for different times at 1 T (d) and 3 T (e).

Figure 5.

MR imaging in vivo at 1 T: after injecting Gd₃₂ (a) and the commercial CA Gd-DTPA (c) into BALB/c mice that received 4T1 tumor cells through the tail vein to establish a tumor model, MRI images of the mice at different time points were obtained. The circular frame indicates the tumor site, and the rectangular frame indicates the kidney site. (b) The distribution of Gd₃₂ in the liver (oval frame). (d) The relative MR signal values of tumors at different time points in mice injected with Gd₃₂ and Gd-DTPA. (e) The relative MR-signal value of the kidney and liver at different time points in a mouse injected with Gd₃₂.