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

Abstract

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.

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

“…Cytotoxicity was found to be low for concentrations as high as 500 μg/mL for PDAC Patient 1 cells, while PC3 cells showed decreased viability at nanoparticle concentrations above 250 μg/mL. The effect is more pronounced after 48 h. It is interesting that the patient-derived PDAC Patient 1 cells are more resistant than the commercially available PC3 cell line, a phenomenon that we have also seen with polyacrylamide nanobeads . However, the many differences in phenotypes of cell lines preclude us from drawing conclusions regarding this resistance.…”

“…The effect is more pronounced after 48 h. It is interesting that the patient-derived PDAC Patient 1 cells are more resistant than the commercially available PC3 cell line, a phenomenon that we have also seen with polyacrylamide nanobeads. 7 However, the many differences in phenotypes of cell lines preclude us from drawing conclusions regarding this resistance.…”

“…Our pioneering cluster-nanocarrier system takes advantage of preformed discrete molecular clusters with magnetically coupled transition metals (Mn and Fe) that are then grafted within a polymer nanocarrier. − Polystyrene was chosen as the nanocarrier based on its established in vitro and in vivo stability and safety, which has led to its wide investigation for drug delivery . The size and monodispersity of pure polystyrene nanobeads are so finely controllable that they have been utilized as a model to investigate the role of size in nano-biointeractions .…”

“…Our prototype for the cluster-nanocarrier is based on the related Mn-Fe-oxo cluster, Mn 8 Fe 4 O 12 (O 2 CCH 3 ) 16 (H 2 O) 4 or Mn 8 Fe 4 , which has a high spin state and aqueous solution stability. We have previously shown that these metal-oxo clusters can have impressive relaxivity that increases when incorporated into a nanocarrier. , Importantly, by confining clusters within a nanocarrier, the rotational correlation time improves relaxivity, and the resulting composite is thermodynamically and chemically inert . Nanocarriers are ideal for the addition of optical probes and/or drugs either on the surface or within the core, for enhanced multimodal targeted detection and therapy.…”

Fabrication of Mn2+-Doped Hollow Mesoporous Aluminosilica Nanoparticles for Magnetic Resonance Imaging and Drug Delivery for Therapy of Colorectal Cancer

“…In recent years, multifunctional nanostructured materials have been applied to cancer diagnosis and therapy [15][16][17][18][19][20][21][22][23]. The dominant advantage of these multifunctional nanomaterials is that they can integrate early cancer diagnosis, targeted drug delivery, and treatment with in vivo tracing and thus improve the anticancer therapeutic efficiency.…”