Application of Manganese Oxide (MnO) nanoparticles in multimodal molecular imaging and cancer therapy: A review

Document Type : Review Paper


1 Department of Medical Physic, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

2 Department of Radiology, Faculty of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran


Contrast agents (CAs) play a critical role in high-resolution magnetic resonance imaging (MRI) applications to enhance the low intrinsic sensitivity of MRI. Manganese oxide nanoparticles (MnO) have gotten developing consideration as substitute spin−lattice (T1) MRI CAs as a result of the Gd-based CAs which are related with renal fibrosis as well as the inherent dark imaging characteristics of superparamagnetic iron oxide NPs. In this review, previous developments in the usage of MnO nanoparticles as MRI CAs for cancer theranostic applications such as developments in toxicological properties, distribution and tumor microenvironment (TME)-responsive biomaterials were reviewed. A literature search was accomplished to discover distributed research that elaborates the use of MnO in multimodal imaging and therapy. In the current study, the electronic search including PubMed/Medline, Embase, ProQuest, Scopus, Cochrane and Google Scholar was performed dependent on Mesh key words. CAs can significantly improve the imaging contrast among the lesions and normal tissues. In this study we generally concentrate on typical advancements of MnO nanoparticles about properties, bimodal or multimodal imaging, and therapy. Numerous researches have demonstrated MnO-based nanostructure produce considerable biocompatibility with the lack of cytotoxicity. Therefore, remarkable features improved photothermal therapy, chemotherapy and Chemodynamic therapy.


1.    Rivlin M, Navon G. Molecular imaging of cancer by glucosamine chemical exchange saturation transfer MRI: A preclinical study. NMR Biomed. 2021; 34(2): e4431.
2.    Mortezazadeh T, Gholibegloo E, Alam NR, Dehghani S, Haghgoo S, Ghanaati H, et al. Gadolinium (III) oxide nanoparticles coated with folic acid-functionalized poly (β-cyclodextrin-co-pentetic acid) as a biocompatible targeted nano-contrast agent for cancer diagnostic: in vitro and in vivo studies. Magn Reson Mater Phy. 2019; 32(4): 487-500.
3.    Mansouri H, Gholibegloo E, Mortezazadeh T, Yazdi MH, Ashouri F, Malekzadeh R, et al. A biocompatible theranostic nanoplatform based on magnetic gadolinium-chelated polycyclodextrin: in vitro and in vivo studies. Carbohydr Polym. 2021; 254: 117262.
4.    Gholibegloo E, Mortezazadeh T, Salehian F, Forootanfar H, Firoozpour L, Foroumadi A, et al. Folic acid decorated magnetic nanosponge: An efficient nanosystem for targeted curcumin delivery and magnetic resonance imaging. J. Colloid Interface Sci. 2019; 556: 128-139.
5.    Narmani A, Farhood B, Haghi-Aminjan H, Mortezazadeh T, Aliasgharzadeh A, Mohseni M, et al. Gadolinium nanoparticles as diagnostic and therapeutic agents: Their delivery systems in magnetic resonance imaging and neutron capture therapy. J Drug Deliv Sci Technol. 2018; 44: 457-466.
6.    Andrade Neto DM, da Costa LS, de Menezes FL, Fechine LMUD, Melo Freire R, Casagrande Denardin J, et al. A novel amino phosphonate-coated magnetic nanoparticle as MRI contrast agent. 2021.
7.    Gallardo-Toledo E, Velasco-Aguirre C, Kogan MJ. Inorganic Nanoparticles and Their Strategies to Enhance Brain Drug Delivery.  Nanomedicines for Brain Drug Delivery: Springer; 2021. p. 149-72.
8.    Mehnati P, Malekzadeh R, Divband B, Yousefi Sooteh M. Assessment of the effect of nano-composite shield on radiation risk prevention to Breast during computed tomography. Iranian Journal of Radiology. 2020; 17(1).
9.    Mortezazadeh T, Gholibegloo E, Riyahi Alam N, Haghgoo S, Musa A, Khoobi M. Glucosamine conjugated gadolinium (III) oxide nanoparticles as a novel targeted contrast agent for cancer diagnosis in MRI. J Biomed Phys Eng. 2020; 10: 25.
10. Addisu KD, Hailemeskel BZ, Mekuria SL, Andrgie AT, Lin Y-C, Tsai H-C. Bioinspired, Manganese-Chelated Alginate–Polydopamine Nanomaterials for Efficient in Vivo T 1-Weighted Magnetic Resonance Imaging. ACS Appl Mater Interfaces. 2018; 10(6): 5147-5160.
11. Xiang Y, Li N, Guo L, Wang H, Sun H, Li R, et al. Biocompatible and pH-sensitive MnO-loaded carbonaceous nanospheres (MnO@ CNSs): A theranostic agent for magnetic resonance imaging-guided photothermal therapy. Carbon. 2018; 136: 113-124.
12. Cai X, Zhu Q, Zeng Y, Zeng Q, Chen X, Zhan Y. Manganese oxide nanoparticles as MRI contrast agents in tumor multimodal imaging and therapy. Int J Nanomedicine. 2019; 14: 8321.
13. Chevallier P, Walter A, Garofalo A, Veksler I, Lagueux J, Begin-Colin S, et al. Tailored biological retention and efficient clearance of pegylated ultra-small MnO nanoparticles as positive MRI contrast agents for molecular imaging. J Mater Chem B. 2014; 2(13): 1779-1790.
14.Huang H, Yue T, Xu K, Golzarian J, Yu J, Huang J. Fabrication and evaluation of tumor-targeted positive MRI contrast agent based on ultrasmall MnO nanoparticles. Colloids Surf B Biointerfaces 2015; 131: 148-154.
15. Li J, Wu C, Hou P, Zhang M, Xu K. One-pot preparation of hydrophilic manganese oxide nanoparticles as T1 nano-contrast agent for molecular magnetic resonance imaging of renal carcinoma in vitro and in vivo. Biosens Bioelectron. 2018; 102: 1-8.
16. Shi S, Chen F, Cai W. Biomedical applications of functionalized hollow mesoporous silica nanoparticles: focusing on molecular imaging. Nanomedicine. 2013; 8(12): 2027-2039.
17. Selvan ST, Patra PK, Ang CY, Ying JY. Synthesis of silica‐coated semiconductor and magnetic quantum dots and their use in the imaging of live cells. Angew Chem. 2007; 119(14): 2500-4.
18.    Liu HM, Wu SH, Lu CW, Yao M, Hsiao JK, Hung Y, et al. Mesoporous silica nanoparticles improve magnetic labeling efficiency in human stem cells. small. 2008; 4(5) :619-626.
19.    Taylor KM, Kim JS, Rieter WJ, An H, Lin W, Lin W. Mesoporous silica nanospheres as highly efficient MRI contrast agents. J Am Chem Soc. 2008; 130(7): 2154-2155.
20.    Kim T, Momin E, Choi J, Yuan K, Zaidi H, Kim J, et al. Mesoporous silica-coated hollow manganese oxide nanoparticles as positive T 1 contrast agents for labeling and MRI tracking of adipose-derived mesenchymal stem cells. J Am Chem Soc. 2011; 133(9): 2955-2961.
21.    Caravan P. Strategies for increasing the sensitivity of gadolinium based MRI contrast agents. Chem So. Rev. 2006; 35(6): 512-523.
22.    Schladt TD, Koll K, Prüfer S, Bauer H, Natalio F, Dumele O, et al. Multifunctional superparamagnetic MnO@ SiO 2 core/shell nanoparticles and their application for optical and magnetic resonance imaging. J Mater Chem. 2012; 22(18): 9253-9262.
23.    Morales M, Skomski R, Fritz S, Shelburne G, Shield JE, Yin M, et al. Surface anisotropy and magnetic freezing of MnO nanoparticles. Phys Rev B. 2007; 75(13): 134423.
24.    Neves HR, Bini RA, Barbosa JH, Salmon CE, Varanda LC. Dextran‐Coated Antiferromagnetic MnO Nanoparticles for a T1‐MRI Contrast Agent with High Colloidal Stability. Particle & Particle Systems Characterization. 2016; 33(3): 167-176.
25.    Hu X, Ji Y, Wang M, Miao F, Ma H, Shen H, et al. Water-soluble and biocompatible MnO@ PVP nanoparticles for MR imaging in vitro and in vivo. J Biomed Nanotechnol. 2013; 9(6): 976-984.
26.    Hsu BYW, Wang M, Zhang Y, Vijayaragavan V, Wong SY, Chang AY-C, et al. Silica–F127 nanohybrid-encapsulated manganese oxide nanoparticles for optimized T 1 magnetic resonance relaxivity. Nanoscale. 2014; 6(1): 293-299.
27.    Douglas FJ, MacLaren DA, Tuna F, Holmes WM, Berry CC, Murrie M. Formation of octapod MnO nanoparticles with enhanced magnetic properties through kinetically-controlled thermal decomposition of polynuclear manganese complexes. Nanoscale. 2014; 6(1): 172-176.
28.    Meng H-M, Lu L, Zhao X-H, Chen Z, Zhao Z, Yang C, et al. Multiple functional nanoprobe for contrast-enhanced bimodal cellular imaging and targeted therapy. Anal Chem. 2015; 87(8): 4448-4454.
29.    Peng Y-K, Lui CN, Chen Y-W, Chou S-W, Raine E, Chou P-T, et al. Engineering of single magnetic particle carrier for living brain cell imaging: a tunable T1-/T2-/dual-modal contrast agent for magnetic resonance imaging application. Chem Mater. 2017; 29(10): 4411-4417.
30.    Wang S, You Q, Wang J, Song Y, Cheng Y, Wang Y, et al. MSOT/CT/MR imaging-guided and hypoxia-maneuvered oxygen self-supply radiotherapy based on one-pot MnO 2-mSiO 2@ Au nanoparticles. Nanoscale. 2019; 11(13): 6270-6284.
31.    Im GH, Kim SM, Lee D-G, Lee WJ, Lee JH, Lee IS. Fe3O4/MnO hybrid nanocrystals as a dual contrast agent for both T1-and T2-weighted liver MRI. Biomaterials. 2013; 34(8): 2069-2076.
32.    Peng E, Wang F, Tan S, Zheng B, Li SFY, Xue JM. Tailoring a two-dimensional graphene oxide surface: dual T 1 and T 2 MRI contrast agent materials. J Mater Chem B. 2015; 3(28): 5678-5682.
33.    Zheng Y, Zhang H, Hu Y, Bai L, Xue J. MnO nanoparticles with potential application in magnetic resonance imaging and drug delivery for myocardial infarction. Int J Nanomedicine. 2018; 13: 6177.
34.    Chen N, Shao C, Li S, Wang Z, Qu Y, Gu W, et al. Cy5. 5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas. J Colloid Interface Sci. 2015; 457: 27-34.
35.    Lai J, Wang T, Wang H, Shi F, Gu W, Ye L. MnO nanoparticles with unique excitation-dependent fluorescence for multicolor cellular imaging and MR imaging of brain glioma. Microchim Acta. 2018; 185(4): 244.
36.    Zhang K, Chen H, Li P, Bo X, Li X, Zeng Z, et al. Marriage strategy of structure and composition designs for intensifying ultrasound & MR & CT trimodal contrast imaging. ACS Appl Mater Interfaces. 2015; 7(33): 18590-18599.
37.    Liu Y, Lv X, Liu H, Zhou Z, Huang J, Lei S, et al. Porous gold nanocluster-decorated manganese monoxide nanocomposites for microenvironment-activatable MR/photoacoustic/CT tumor imaging. Nanoscale. 2018; 10(8): 3631-3638.
38.    Liu J-n, Bu W, Shi J. Chemical design and synthesis of functionalized probes for imaging and treating tumor hypoxia. Chem rev. 2017; 117(9): 6160-6224.
39.    Ni D, Jiang D, Valdovinos HF, Ehlerding EB, Yu B, Barnhart TE, et al. Bioresponsive polyoxometalate cluster for redox-activated photoacoustic imaging-guided photothermal cancer therapy. Nano lett. 2017; 17(5): 3282-3289.
40. Hussein EA, Zagho MM, Nasrallah GK, Elzatahry AA. Recent advances in functional nanostructures as cancer photothermal therapy. International journal of nanomedicine. 2018; 13: 2897.
41.    Hussein EA, Zagho MM, Nasrallah GK, Elzatahry AA. Recent advances in functional nanostructures as cancer photothermal therapy. Int J Nanomedicine. 2018; 13: 2897.
42.    Wang S, Zhang Q, Yang P, Yu X, Huang L-Y, Shen S, et al. Manganese oxide-coated carbon nanotubes as dual-modality lymph mapping agents for photothermal therapy of tumor metastasis. ACS Appl Mater. 2016; 8(6): 3736-3743.
43.    Zhou L, Wu Y, Meng X, Li S, Zhang J, Gong P, et al. Dye‐Anchored MnO Nanoparticles Targeting Tumor and Inducing Enhanced Phototherapy Effect via Mitochondria‐Mediated Pathway. Small. 2018; 14(36): 1801008.
44.    Zhao C-Y, Cheng R, Yang Z, Tian Z-M. Nanotechnology for cancer therapy based on chemotherapy. Molecules. 2018; 23(4): 826.
45.    Lu Y, Zhang L, Li J, Su YD, Liu Y, Xu YJ, et al. MnO nanocrystals: a platform for integration of MRI and genuine autophagy induction for chemotherapy. Adv Funct Mater. 2013; 23(12): 1534-1546.
46.    Wei J, Yu C, Wang L, Wang J, Zhou Z, Yang H, et al. Cytotoxicity of mitochondrial-targeting silica-coated manganese oxide nanoparticles. Sci China Chem. 2015; 58(10): 1537-1543.
47.    Howell M, Mallela J, Wang C, Ravi S, Dixit S, Garapati U, et al. Manganese-loaded lipid-micellar theranostics for simultaneous drug and gene delivery to lungs. J Control Release. 2013; 167(2): 210-218.
48.    Abbasi AZ, Prasad P, Cai P, He C, Foltz WD, Amini MA, et al. Manganese oxide and docetaxel co-loaded fluorescent polymer nanoparticles for dual modal imaging and chemotherapy of breast cancer. J Control Release. 2015; 209: 186-196.
49.    Lin L-S, Huang T, Song J, Ou X-Y, Wang Z, Deng H, et al. Synthesis of copper peroxide nanodots for H2O2 self-supplying chemodynamic therapy. J Am Chem Soc. 2019; 141(25): 9937-9945.
50.    Choi JY, Lee SH, Na HB, An K, Hyeon T, Seo TS. In vitro cytotoxicity screening of water-dispersible metal oxide nanoparticles in human cell lines. Bioproc Biosystems Eng. 2010; 33(1): 21.
51.    Yang B, Liu Q, Yao X, Zhang D, Dai Z, Cui P, et al. FePt@ MnO-based nanotheranostic platform with acidity-triggered dual-ions release for enhanced MR imaging-guided ferroptosis chemodynamic therapy. ACS Appl Mater Interfaces. 2019; 11(42): 38395-38404.
52.    Marques JP, Simonis FF, Webb AG. Low‐field MRI: An MR physics perspective. J Magn Reson Imaging. 2019; 49(6): 1528-1542.
53. Hajesmaeelzadeh F, Shanehsazzadeh S, Grüttner C, Daha FJ, Oghabian MA. Effect of coating thickness of iron oxide nanoparticles on their relaxivity in the MRI. Iran J Basic Med Sci. 2016; 19(2): 166.
54. Mauri M, Collico V, Morelli L, Das P, Garcia I, Penaranda Avila J, et al. MnO Nanoparticles Embedded in Functional Polymers as T 1 Contrast Agents for Magnetic Resonance Imaging. ACS Appl Nano Mater. 2020; 3(4): 3787-3797.
55. Hsu BYW, Kirby G, Tan A, Seifalian AM, Li X, Wang J. Relaxivity and toxicological properties of manganese oxide nanoparticles for MRI applications. RSC adv. 2016; 6(51): 45462-45474.
56. Cai X, Zhu Q, Zeng Y, Zeng Q, Chen X, Zhan Y. Manganese Oxide Nanoparticles As MRI Contrast Agents In Tumor Multimodal Imaging And Therapy. Int J Nanomed. 2019; 14:8321-8344.
57. Shin J, Anisur RM, Ko MK, Im GH, Lee JH, Lee IS. Hollow manganese oxide nanoparticles as multifunctional agents for magnetic resonance imaging and drug delivery. Angew Chem Int. 2009; 48(2): 321-324.
58. Chaturvedi A, Pranjali P, Meher MK, Raj R, Basak M, Singh RK, et al. In vitro and ex vivo relaxometric properties of ethylene glycol coated gadolinium oxide nanoparticles for potential use as contrast agents in magnetic resonance imaging. J Appl Phys. 2020;128(3):034903.
59. Caravan P, Farrar CT, Frullano L, Uppal R. Influence of molecular parameters and increasing magnetic field strength on relaxivity of gadolinium‐and manganese‐based T1 contrast agents. Contrast Media Mol Imaging. 2009; 4(2): 89-100.
60. Bloembergen N, Morgan L. Proton relaxation times in paramagnetic solutions. Effects of electron spin relaxation. J Chem Phys. 1961; 34(3): 842-850.
61. Zhou Z, Yang L, Gao J, Chen X. Structure–relaxivity relationships of magnetic nanoparticles for magnetic resonance imaging. ADV MATER. 2019; 31(8): 1804567.
62. Pan D, Schmieder AH, Wickline SA, Lanza GM. Manganese-based MRI contrast agents: past, present and future. Tetrahedron. 2011; 67(44): 8431.
63. Ding B, Yu C, Li C, Deng X, Ding J, Cheng Z, et al. cis-Platinum pro-drug-attached CuFeS 2 nanoplates for in vivo photothermal/photoacoustic imaging and chemotherapy/photothermal therapy of cancer. Nanoscale. 2017; 9(43): 16937-16949.
64. De León‐Rodríguez LM, Martins AF, Pinho MC, Rofsky NM, Sherry AD. Basic MR relaxation mechanisms and contrast agent design. J Magn Reson Imaging. 2015; 42(3): 545-565.
65. Gallez B, Bacic G, Swartz HM. Evidence for the dissociation of the hepatobiliary MRI contrast agent Mn‐DPDP. Magn Reson Med. 1996; 35(1): 14-19.
66. Gilad AA, Walczak P, McMahon MT, Na HB, Lee JH, An K, et al. MR tracking of transplanted cells with “positive contrast” using manganese oxide nanoparticles. Magn Reson Med: An Official Journal of the International Society for Magnetic Resonance in Medicine. 2008; 60(1): 1-7.
67. Na HB, Lee JH, An K, Park YI, Park M, Lee IS, et al. Cover Picture: Development of a T1 Contrast Agent for Magnetic Resonance Imaging Using MnO Nanoparticles (Angew. Chem. Int. Ed. 28/2007). Angew Chem Int Ed. 2007; 46(28): 5247.
68. Schladt TD, Schneider K, Shukoor MI, Natalio F, Bauer H, Tahir MN, et al. Highly soluble multifunctional MnO nanoparticles for simultaneous optical and MRI imaging and cancer treatment using photodynamic therapy. J Mater Chemry. 2010; 20(38): 8297-8304.