New nanosized biocompatible MR contrast agents based on lysine-dendri-graft macromolecules

Abstract

Paramagnetic nanomaterials for use as magnetic resonance imaging (MRI) contrast agents have higher relaxivity than conventional low molecular weight MRI agents. However, the biocompatibility and pharmacokinetics of such nanomaterials will strongly affect the likelihood of clinical approval. We synthesized MRI contrast agents based on biocompatible lysine-dendri-grafts: Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3. The relaxivity of Gd-BzDTPA-lysineG2 and Gd-BzDTPA-lysineG3 increased with sample temperature, while the relaxivity of Gd-BzDTPA-PAMAMG4 decreased with increasing sample temperature. The increase in relaxivity with increasing temperature may be attributed to accessibility of water to the internal Gd chelates with lysine-dendri-grafts, which does not occur with PAMAM dendrimers. Gd-BzDTPA-lysineG3 had a long intravascular half-life but were largely excreted by the kidneys. Therefore, Gd-BzDTPA-lysineG3 enhanced the blood vessels for longer periods than Gd-BzDTPA-PAMAMG4, but was still excreted through the kidney. Because of their biocompatibility, desirable magneto-physical characteristics and favorable pharmacokinetics, which are derived from different interior structures rather than the physical size, lysine-dendri-graft MR contrast agents may be feasible for clinical use.

Figure 1

Synthetic scheme of Gd-BzDTPA-lysineG3.

Figure 2

Frequency dependency of r1 (A) and r2 (B) profiles for each contrast agent at 23 °C.

Figure 3

Temperature dependency r1 (A) and r2 (B) profiles for each contrast agent at 35 MHz.

Figure 4

Biodistribution of [¹¹¹In]Gd-BzDTPA-lysineG2 (A), [¹¹¹In]Gd-BzDTPA-lysineG3 (B) and [¹¹¹In]Gd-BzDTPA-PAMAMG4 (C) in mice.

Figure 5

Plots of the signal intensity in the jugular vein, the liver, the cortex and medulla of the kidney and the muscle at the femoral region obtained from the contrast enhanced dynamic MRI of mice; Gd-BzDTPA-lysineG2 (A), Gd-BzDTPA-lysineG3 (B) and Gd-BzDTPA-PAMAMG4 (C).

Figure 6

The whole body 3D MR images of mice, which were constructed with the MIP method with preinjection (left), immediately after (middle) and 50 min after (right) injection of Gd-BzDTPA-lysineG2 (A), Gd-BzDTPA-lysineG3 (B) or Gd-BzDTPA-PAMAMG4 (C).