Urchin‐Shaped Manganese Oxide Nanoparticles as pH‐Responsive Activatable T₁ Contrast Agents for Magnetic Resonance Imaging

Abstract

The ultrasensitive detection of cancer in its earliest stage would greatly help the ensuing treatment process, and therefore various imaging modalities and image-enhancing methods are being developed.[1] In particular, metal oxide nanoparticles prove to be promising contrast agents in magnetic resonance imaging (MRI) for the ultrasensitive detection of cancer, and the principles for enhancing MRI contrast have been deciphered recently.[2] For example, it is advantageous to employ superparamagnetic metal oxide nanoparticles with high magnetization values (emu g À1 ) for improved T 2 image contrast.[3] In addition, clusters of superparamagnetic nanoparticles exhibit greater T 2 contrast abilities than individual nanoparticles.[4] Therefore, the clustering of magnetic nanoparticles with high magnetization values is advantageous because of both improved T 2 contrast and the frugal usage of targeting moieties. For enhanced T 1 contrast, nanoparticles should have numerous high-spin metal ions exposed on the surface for facilitated interactions with the surrounding water molecules. [5,6] This calls for the use of smaller nanoparticles with a high surface-to-volume ratio, but simply using a high number of small nanoparticles is not compatible with the frugal usage of targeting moieties. In the case of large nanoparticles, the non-exposed metal ions in the core cannot contribute to the MRI T 1 contrast; the T 1 -weighted image obtained with metal ions is much poorer than that from conventional ion-based contrast agents.We reasoned that the highest surface area for a nanoparticle of a given diameter would be provided by an urchinlike morphology as shown in Figure 1. As a model system to prove our concept, manganese oxides were investigated that had been previously used as an MRI T 1 contrast agent. This system is particularly interesting because of the easy conversion of MnO to Mn 3 O 4 and the different stabilities of these two manganese oxide phases under physiological conditions. It is envisaged that the MnO nanoparticle trapped in the thin shell of an urchin-shaped stable Mn 3 O 4 phase can be unloaded in the form of Mn II ions to the low-pH sites (< pH 7) in the tumor. While the low pH of tumor cells has been exploited for the fabrication of numerous activatable drug-delivery systems, [7] a nanoparticle-based pH-activatible MRI agent is unprecedented to our knowledge. The combination of the T 1 contrast effect from the empty Mn 3 O 4 urchin shell with a high surface area and the released Mn II ions should make the MnO@Mn 3 O 4 nanourchin a powerful MRI T 1 contrast agent. Herein we report the synthesis of the MnO@Mn 3 O 4 nanourchin through facet-selective etching as well as its successful application as a pH-responsive activatable T 1 contrast agent,

Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

“…54,55,63,133 The size-dependent magnetic properties of MnO and Mn 3 O 4 NPs with monodispersed sizes in the range of 6–22 nm were initially reported by Seo et al . 134 Subsequently, the size-dependent T 1 relaxation properties of MnO NPs were investigated by Hyeon and co-workers, 69 demonstrating higher T 1 signal enhancement for smaller MnO NPs than larger ones (Fig.…”

“…61,63 For example, Kim et al . reported core–shell Fe 3 O 4 @Mn 3 O 4 NPs, where Mn 2+ ions released from the Mn 3 O 4 shell under reducing conditions allowed Fe 3 O 4 NPs to interact with water protons, thereby enhancing contrast of both T 1 and T 2 -weighted MRI.…”

Near-infrared light-triggered theranostics for tumor-specific enhanced multimodal imaging and photothermal therapy

“…However, the intrinsic limitation about poor soft tissue resolutions, radiation, and renal toxicity of commercial CAs have limited commercial CAs clinical application. 3,4 In order to improve the modest signal/noise ratio of cancerous tissues, lots of carriers, which are responsive to such external stimuli as pH, [5][6][7] redox, 8 temperature, 9 enzyme, 10 and competitive binding, 11 have been developed. Nevertheless, acquiring tumor imaging specifically, spatially and temporally has been still a big challenge for CAs.…”

Redoxable heteronanocrystals functioning magnetic relaxation switch for activatable T1 and T2 dual-mode magnetic resonance imaging

“…MR imaging is particularly appealing because it can provide anatomical images of tissues and organs with excellent spatial resolution [3,4]. The diagnostic capabilities of MR imaging can be greatly improved by introducing exogenous medical media, such as T 1 or T 2 contrast agents, for enhanced target tissue contrast on T 1 -or T 2 -weighted imaging sequences, respectively [5,6]. T 1 contrast agents, represented by clinically-available gadolinium (Gd 3þ ) chelates, are paramagnetic materials, which shorten the longitudinal relaxation time (T 1 ) of nearby water protons [7,8].…”