Method for increasing dispersion stability of nanoparticles as T1 MRI contrast agent and T1 MRI contrast nanoparticles
The present invention improves an existing contrast agent, especially, a T1 contrast agent, and adopts a strategy in which the T1 contrast material is partially coated on a support surface to which a hydrophilic functional group is exposed. The partial coating strategy adopted in the present invention improves both the stability and contrast performance of T1 contrast agent nanoparticles, and such a strategy leads to very interesting technical development.
1 . A method of preparing a druggable T1 contrast agent, the method comprising:
(a) cross-linking dextran using epichlorohydrin and an amine cross-linking agent to provide a support particle, comprising hydrophilic chemical functional groups exposed on its surface, wherein
(i) the hydrophilic chemical functional groups comprise amine groups; and
(ii) the hydrodynamic size of the support particle is from 1-8 nm;
(b) coordinating a T1 contrast material comprising Fe 2+ , Fe 3+ , or combination thereof on 20% or fewer of hydrophilic functional groups on the surface of the support particle to provide a particlized T1 contrast agent, wherein the hydrodynamic size of the particlized contrast agent is 2-6 nm; and
(c) substituting the amine groups with carboxyl groups to provide the druggable T1 contrast agent;
wherein the druggable T1 contrast agent of step (c) has reduced toxicity when intravenously administered relative to the particlized T1 contrast agent of step (b).
2 . The method of claim 1 , wherein the hydrodynamic size of the support particles is from 1-5 nm, 1-4 nm, 2-8 nm, 2-5 nm, 2-4 nm, 3-8 nm, 3-5 nm, 3-4 nm, 4-8 nm, 4-7 nm, or 4-5 nm.
3 . The method of claim 1 , wherein the hydrodynamic size of the particlized contrast agent is 2-5 nm, 3-6 nm, 3-5 nm, or 4-6 nm.
4 . The method of claim 1 , wherein the T1 contrast material is an iron oxide.
5 . The method of claim 1 , wherein in step b, the amount of the T1 contrast material used relative to the weight of the support particles is from 0.5-10 wt %, 0.8-7.0 wt % 0.5-5.0 wt %, or 0.9-5.0 wt %.
6 . The method of claim 1 , wherein the particlized T1 contrast agent showed dispersion stability in which the hydrodynamic size change is ±10% or less when exposed to (i) a NaCl concentration change between 125 mM to 500 mM in an aqueous solution at constant pH and room temperature; (ii) a ±10% or less for a change between pH 6 and pH 8 in an aqueous solution of 0.1M NaCl at room temperature; and (iii) ±10% or less for a temperature range between 4° C. and 37° C. in phosphate buffered saline at pH 7.4.
7 . The method of claim 1 , wherein the T 1 contrast material is a metal.
8 . The method of claim 7 , wherein the particlized contrast agent exhibits a T 1 relaxivity of 2.7-5.0 s−1 for 1 mM concentration of iron in a field strength of 3T.
9 . The method of claim 8 , wherein the T 1 contrast material is an iron oxide.
10 . The method of claim 9 , wherein the T 1 contrast material is Fe 3 O 4 .
11 . The method of claim 4 , wherein the T 1 contrast material is Fe 3 O 4 .
12 . The method of claim 1 , wherein the druggable T1 contrast agent exhibits reduced toxicity in the body relative to a reference T1 contrast agent.