Kinetically inert manganese (II)-based hybrid micellar complexes for magnetic resonance imaging of lymph node metastasis

Abstract

The localization and differential diagnosis of the sentinel lymph nodes (SLN) are particularly important for tumor staging, surgical planning, and prognosis. In this work, kinetically inert manganese (II) -based hybrid micellar complexes (MnCs) for magnetic resonance imaging were developed using an amphiphilic manganese-based chelate (C18-PhDTA-Mn) with reliable kinetic stability and self-assembled with a series of amphiphilic PEG-C18 polymers of different molecular weights (C18En, n = 10, 20, 50). Among them, the probes composed by 1:10 mass ratio of manganese chelate/C18En had slightly different hydrodynamic particle sizes with similar surface charges as well as considerable relaxivities (∼13 mM−1s−1 at 1.5 T). In vivo lymph node imaging in mice revealed that the micellar complex MnC-20 formed by C18E20 with C18-PhDTA-Mn at a hydrodynamic particle size of 5.5 nm had significant signal intensity brightening effect and shortened T 1 relaxation time. At an imaging probe dosage of 125 μg Mn/kg, lymph nodes still had significant signal enhancement in 2 hours, while there is no obvious signal intensity alteration in non-lymphoid regions. In 4T1 tumor metastatic mice model, sentinel lymph nodes showed less signal enhancement and smaller T 1 relaxation time variation at 30 min post injection, when compared with normal lymph nodes. This was favorable to differentiate normal lymph nodes from SLN under a 3.0 T clinical MRI scanner. In conclusion, the strategy of developing manganese-based MR nanoprobes was useful in lymph node imaging.

Mn-Based MRI Contrast Agents: An Overview

“…As described previously [81][82][83][84], amphiphilic Mn complexes can be assembled in lipidic nanoobjects, such as micelles or liposomes, with considerable relaxivities. For example, Ai et al [84] co-assembled amphiphilic Mn chelates (C18-PhDTA-Mn) with amphiphilic PEG-C18 polymers to obtain mixed micelles of different hydrodynamic sizes and relaxivities up to 13 s −1 mM −1 at 1.5T and 25 • C.…”

“…Nevertheless, as already mentioned in the previous section concerning the small Mn complexes, very few toxicity data are available. Again, some studies present encouraging cytotoxic studies on various cell lines [84,103,104,108] which do not show any acute toxic effect. We can also cite the study of Ai et al [83], who measured key serum biochemical indicators of liver function and kidney function and found a normal range for all of them.…”

“…Furthermore, micelles were able to interact with HSA, increasing even more the relaxivity. In another study, PEGylated amphiphilic polymeric Mn complexes were developed and showed an enhanced relaxivity as well as an excellent and relatively long-time-window vascular enhancement effect [83,84].…”