Abstract
Manganese oxide (MnO) nanoparticles (NPs) can serve as robust pH-sensitive contrast agents for magnetic resonance imaging (MRI) due to Mn2+ release at low pH, which generates a ~30 fold change in T1 relaxivity. Strategies to control NP size, composition, and Mn2+ dissolution rates are essential to improve diagnostic performance of pH-responsive MnO NPs. We are the first to demonstrate that MnO NP size and composition can be tuned by the temperature ramping rate and aging time used during thermal decomposition of manganese(II) acetylacetonate. Two different temperature ramping rates (10°C/min and 20°C/min) were applied to reach 300°C and NPs were aged at that temperature for 5, 15, or 30 min. A faster ramping rate and shorter aging time produced the smallest NPs of ~23 nm. Shorter aging times created a mixture of MnO and Mn3O4 NPs, whereas longer aging times formed MnO. Our results indicate that a 20°C/min ramp rate with an aging time of 30 min was the ideal temperature condition to form the smallest pure MnO NPs of ~32 nm. However, Mn2+ dissolution rates at low pH were unaffected by synthesis conditions. Although Mn2+ production was high at pH 5 mimicking endosomes inside cells, minimal Mn2+ was released at pH 6.5 and 7.4, which mimic the tumor extracellular space and blood, respectively. To further elucidate the effects of NP composition and size on Mn2+ release and MRI contrast, the ideal MnO NP formulation (~32 nm) was compared with smaller MnO and Mn3O4 NPs. Small MnO NPs produced the highest amount of Mn2+ at acidic pH with maximum T1 MRI signal; Mn3O4 NPs generated the lowest MRI signal. MnO NPs encapsulated within poly(lactide-co-glycolide) (PLGA) retained significantly higher Mn2+ release and MRI signal compared to PLGA Mn3O4 NPs. Therefore, MnO instead of Mn3O4 should be targeted intracellularly to maximize MRI contrast.
Highlights
The use of metal oxide nanoparticles (NPs) has been increasing over the past decades due to their magnetic, electric, and catalytic properties
We are the first to demonstrate that modification of the temperature ramp rate and aging time at 300 ̊C can be used to fine-tune both the diameter and composition of manganese oxide (MnO) NPs (Fig 10)
To achieve pure MnO, which is most desirable for magnetic resonance imaging (MRI) applications, longer aging times at 300 ̊C were needed, but MnO NP size increased as well
Summary
The use of metal oxide nanoparticles (NPs) has been increasing over the past decades due to their magnetic, electric, and catalytic properties. Of particular interest to biomedical applications is the ability of metal oxide NPs, such as iron oxide and manganese oxide (MnO), to serve as contrast agents for magnetic resonance imaging (MRI) [1]. Iron oxide NPs are superparamagnetic and cause dark contrast on T2 and T2 MRI. Iron oxide NPs elicit strong MRI signal in their intact form and constantly generate contrast, or are always in the “ON” state. Our group and other studies have shown that intact MnO NPs are in an “OFF” state and create minimal T1 MRI signal due to the Mn2+ ions being tightly bound and inaccessible to the surrounding water molecules [5,6,7,8,9,10]. MnO dissolves to form Mn2+, which coordinates with water molecules to decrease T1 and produce a positive MRI signal, turning “ON” MRI contrast [5,6,7,8,9,10]
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