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Theranostics 2019; 9(6):1764-1776. doi:10.7150/thno.31233 This issue Cite

Research Paper

Composition-Tunable Ultrasmall Manganese Ferrite Nanoparticles: Insights into their In Vivo T₁ Contrast Efficacy

Yuqing Miao^1*, Qian Xie^2*, Huan Zhang¹, Jing Cai³, Xiaoli Liu¹, Ju Jiao⁴, Shanshuang Hu⁵, Anujit Ghosal¹, Yu Yang⁵, Haiming Fan^1✉

1. Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an, Shaanxi 710069, China.
2. Division of nephrology, Peking University Third Hospital, Beijing, China.
3. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
4. Department of Nuclear Medicine, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Guangzhou, Guangdong 510630, China.
5. School of Life Sciences, National Engineering Research Center for Miniaturized Detection Systems, Northwest University, Xi'an, Shaanxi, China.
*Yuqing Miao and Qian Xie have equal contribution.

✉ Corresponding author: fanhmedu.cn

Abstract

The development of a highly efficient, low-toxicity, ultrasmall ferrite nanoparticle-based T₁ contrast agent for high-resolution magnetic resonance imaging (MRI) is highly desirable. However, the correlations between the chemical compositions, in vitro T₁ relaxivities, in vivo nano-bio interactions and toxicities remain unclear, which has been a challenge in optimizing the in vivo T₁ contrast efficacy.

Methods: Ultrasmall (3 nm) manganese ferrite nanoparticles (Mn_xFe_3-xO₄) with different doping concentrations of the manganese ions (x = 0.32, 0.37, 0.75, 1, 1.23 and 1.57) were used as a model system to investigate the composition-dependence of the in vivo T₁ contrast efficacy. The efficacy of liver-specific contrast-enhanced MRI was assessed through systematic multiple factor analysis, which included the in vitro T₁ relaxivity, in vivo MRI contrast enhancement, pharmacokinetic profiles (blood half-life time, biodistribution) and biosafety evaluations (in vitro cytotoxicity testing, in vivo blood routine examination, in vivo blood biochemistry testing and H&E staining to examine the liver).

Results: With increasing Mn doping, the T₁ relaxivities initially increased to their highest value of 10.35 mM^-1s^-1, which was obtained for Mn_0.75Fe_2.25O₄, and then the values decreased to 7.64 m M^-1s^-1, which was obtained for the Mn_1.57Fe_1.43O₄ nanoparticles. Nearly linear increases in the in vivo MRI signals (ΔSNR) and biodistributions (accumulation in the liver) of the Mn_xFe_3-xO₄ nanoparticles were observed for increasing levels of Mn doping. However, both the in vitro and in vivo biosafety evaluations suggested that Mn_xFe_3-xO₄ nanoparticles with high Mn-doping levels (x > 1) can induce significant toxicity.

Conclusion: The systematic multiple factor assessment indicated that the Mn_xFe_3-xO₄ (x = 0.75-1) nanoparticles were the optimal T₁ contrast agents with higher in vivo efficacies for liver-specific MRI than those of the other compositions of the Mn_xFe_3-xO₄ nanoparticles. Our work provides insight into the optimization of ultrasmall ferrite nanoparticle-based T₁ contrast agents by tuning their compositions and promotes the translation of these ultrasmall ferrite nanoparticles for clinical use of high-performance contrast-enhanced MRI.

Keywords: ultrasmall ferrite nanoparticles, composition effect, MRI, in vivo T₁ contrast efficacy

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