Molecular Parameters Promoting High Relaxivity in Cluster-Nanocarrier Magnetic Resonance Imaging Contrast Agents.

We have investigated the mechanism of relaxivity for two magnetic resonance imaging contrast agents that both employ a cluster-nanocarrier design. The first system termed Mn8Fe4-coPS comprises the cluster Mn8Fe4O12(L)16(H2O)4 or Mn8Fe4 (1) (L = carboxylate) co-polymerized with polystyrene to form ∼75 nm nanobeads. The second system termed Mn3Bpy-PAm used the cluster Mn3(O2CCH3)6(Bpy)2 or Mn3Bpy (2) where Bpy = 2,2'-bipyridine, entrapped in ∼180 nm polyacrylamide nanobeads. Here, we investigate the rate of water exchange of the two clusters, and corresponding cluster-nanocarriers, in order to elucidate the mechanism of relaxivity in the cluster-nanocarrier. Swift-Connick analysis of O-17 NMR was used to determine the water exchange rates of the clusters and cluster-nanocarriers. We found distinct differences in the water exchange rate between Mn8Fe4 and Mn8Fe4-coPS, and we utilized these differences to elucidate the nanobead structure. Using the transverse relaxivity from O-17 NMR line widths, we were able to determine the hydration state of the Mn3Bpy (2) cluster as well as Mn3Bpy-PAm. Using these hydration states in the Swift-Connick analysis of O-17 NMR, we found the water exchange rate to be extremely close in value for the cluster Mn3Bpy and cluster-nanocarrier Mn3Bpy-PAm.

Paramagnetic Mn8Fe4-co-Polystyrene Nanobeads as a Potential T1-T2 Multimodal Magnetic Resonance Imaging Contrast Agent with In Vivo Studies.

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 Mn8Fe4O12(O2CC6H4CH═CH2)16(H2O)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; r1 increases from 3.8 to 5.2 ± 0.1 mM-1 s-1, and r2 increases from 11.9 to 50.1 ± 4.8 mM-1 s-1, at 9.4 teslas, strengthening the potential for T1 and T2 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.

Paramagnetic Clusters of Mn3(O2CCH3)6(Bpy)2 in Polyacrylamide Nanobeads as a New Design Approach to a T1- T2 Multimodal Magnetic Resonance Imaging Contrast Agent.

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 Mn3(O2CCH3)6(Bpy)2 (1) where Bpy = 2,2'-bipyridine and three new analogs, Mn3(O2CC6H4CH═CH2)6(Bpy)2 (2), Mn3(O2CC(CH3)═CH2)6(Bpy)2 (3), and Mn3O(O2CCH3)6(Pyr)2 (4) where Pyr = pyridine. The parent cluster, Mn3(O2CCH3)6(Bpy)2 (1), had impressive relaxivity ( r1 = 6.9 mM-1 s-1, r2 = 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 Mn3Bpy-PAm). The nanobeads were surface-modified 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 r1 = 54.4 mM-1 s-1 and r2 = 144 mM-1 s-1, surpassing T1 relaxivity of clinically used Gd-DTPA chelates as well as comparable T2 relaxivity to iron oxide microspheres. Physicochemical properties, cellular uptake, and impacts on cell viability were also investigated.