There is an increasing need for gadolinium-free magnetic resonance imaging (MRI) contrast agents, particularly for patients suffering from chronic kidney disease. Using a cluster−nanocarrier combination, we have identified a novel approach to the design of biomedical nanomaterials and report here the criteria for the cluster and the nanocarrier and the advantages of this combination. We have investigated the relaxivity of the following manganese oxo clusters: the parent cluster Mn 3 (O 2 CCH 3 ) 6 (Bpy) 2 (1) where Bpy = 2,2′-bipyridine and three new analogs, Mn 3 (O 2 CC 6 H 4 CHCH 2 ) 6 (Bpy) 2 (2), Mn 3 (O 2 CC(CH 3 )CH 2 ) 6 (Bpy) 2 (3), and Mn 3 O(O 2 CCH 3 ) 6 (Pyr) 2 (4) where Pyr = pyridine. The parent cluster, Mn 3 (O 2 CCH 3 ) 6 (Bpy) 2 (1), had impressive relaxivity (r 1 = 6.9 mM −1 s −1 , r 2 = 125 mM −1 s −1 ) and was found to be the most amenable for the synthesis of cluster-nanocarrier nanobeads. Using the inverse miniemulsion polymerization technique (1) in combination with the hydrophilic monomer acrylamide, we synthesized nanobeads (∼125 nm diameter) with homogeneously dispersed clusters within the polyacrylamide matrix (termed Mn 3 Bpy-PAm). The nanobeads were surfacemodified by co-polymerization with an amine-functionalized monomer. This enabled various postsynthetic modifications, for example, to attach a near-IR dye, Cyanine7, as well as a targeting agent. When evaluated as a potential multimodal MRI contrast agent, high relaxivity and contrast were observed with r 1 = 54.4 mM −1 s −1 and r 2 = 144 mM −1 s −1 , surpassing T 1 relaxivity of clinically used Gd-DTPA chelates as well as comparable T 2 relaxivity to iron oxide microspheres. Physicochemical properties, cellular uptake, and impacts on cell viability were also investigated.

In developing a cluster-nanocarrier design, as a magnetic resonance imaging contrast agent, we have investigated the enhanced relaxivity of a manganese and iron-oxo cluster grafted within a porous polystyrene nanobead with increased relaxivity due to a higher surface area. The synthesis of the cluster-nanocarrier for the cluster Mn 8 Fe 4 O 12 (O 2 CC 6 H 4 CHCH 2 ) 16 (H 2 O) 4 , cross-linked with polystyrene (the nanocarrier), under miniemulsion conditions is described. By including a branched hydrophobe, iso-octane, the resulting nanobeads are porous and ∼70 nm in diameter. The increased surface area of the nanobeads compared to nonporous nanobeads leads to an enhancement in relaxivity; r 1 increases from 3.8 to 5.2 ± 0.1 mM −1 s −1 , and r 2 increases from 11.9 to 50.1 ± 4.8 mM −1 s −1 , at 9.4 teslas, strengthening the potential for T 1 and T 2 imaging. Several metrics were used to assess stability, and the porosity produced no reduction in metal stability. Synchrotron X-ray fluorescence microscopy was used to demonstrate that the nanobeads remain intact in vivo. In depth, physicochemical characteristics were determined, including extensive pharmacokinetics, in vivo imaging, and systemic biodistribution analysis.

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