We present the MR properties of a novel bio-responsive phosphorus probe doped with iron for dual proton and phosphorus magnetic resonance imaging (1H/31P-MRI), which provide simultaneously complementary information. The probes consist of non-toxic biodegradable calcium phytate (CaIP6) nanoparticles doped with different amounts of cleavable paramagnetic Fe3+ ions. Phosphorus atoms in the phytate structure delivered an efficient 31P-MR signal, with iron ions altering MR contrast for both 1H and 31P-MR. The coordinated paramagnetic Fe3+ ions broadened the 31P-MR signal spectral line due to the short T2 relaxation time, resulting in more hypointense signal. However, when Fe3+ was decomplexed from the probe, relaxation times were prolonged. As a result of iron release, intensity of 1H-MR, as well as the 31P-MR signal increase. These 1H and 31P-MR dual signals triggered by iron decomplexation may have been attributable to biochemical changes in the environment with strong iron chelators, such as bacterial siderophore (deferoxamine). Analysing MR signal alternations as a proof-of-principle on a phantom at a 4.7 T magnetic field, we found that iron presence influenced 1H and 31P signals and signal recovery via iron chelation using deferoxamine.

Department of Diagnostic and Interventional Radiology MR unit Institute for Clinical and Experimental Medicine Prague Czech Republic

Faculty of Mechatronics Informatics and Interdisciplinary Studies Technical University of Liberec Liberec Czech Republic

Institute of Biophysics and Informatics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Macromolecular Chemistry Czech Academy of Sciences Prague Czech Republic

See more in PubMed

Hasebroock KM, Serkova NJ. Toxicity of MRI and CT contrast agents. Expert Opin. Drug Metab. Toxicol. 2009;5:403–416. doi: 10.1517/17425250902873796. PubMed DOI

Jeong Y, Hwang HS, Na K. Theranostics and contrast agents for magnetic resonance imaging. Biomater. Res. 2018;22:1. doi: 10.1186/s40824-017-0112-8. PubMed DOI PMC

Benyettou F, et al. A multimodal magnetic resonance imaging nanoplatform for cancer theranostics. Phys. Chem. Chem. Phys. 2011;13:10020–10027. doi: 10.1039/c0cp02034f. PubMed DOI

An L, Cai Y, Tian Q, Lin J, Yang S. Ultrasensitive iron-based magnetic resonance contrast agent constructed with natural polyphenol tannic acid for tumor theranostics. Sci. China Mater. 2021;64:498–509. doi: 10.1007/s40843-020-1434-1. DOI

Sedlacek O, et al. Fluorinated water-soluble poly(2-oxazoline)s as highly sensitive 19F MRI contrast agents. Macromolecules. 2020;53:6387–6395. doi: 10.1021/acs.macromol.0c01228. DOI

Kolouchova K, et al. Implant-forming polymeric 19F MRI-tracer with tunable dissolution. J. Control. Release. 2020;327:50–60. doi: 10.1016/j.jconrel.2020.07.026. PubMed DOI

Hu R, et al. X-nuclei imaging: Current state, technical challenges, and future directions. J. Magn. Reson. Imaging. 2020;51:355–376. doi: 10.1002/jmri.26780. PubMed DOI

Fox MS, Gaudet JM, Foster PJ. Fluorine-19 MRI contrast agents for cell tracking and lung imaging. Magn. Reson. Insights. 2015;8:53–67. PubMed PMC

Santos-Díaz, A. & Noseworthy, M. D. Phosphorus magnetic resonance spectroscopy and imaging (31P-MRS/MRSI) as a window to brain and muscle metabolism: A review of the methods. Biomed. Signal Process. Control60, 101967 (2020).

Sedivy P, et al. MR compatible ergometers for dynamic 31P MRS. J. Appl. Biomed. 2019;17:91–98. doi: 10.32725/jab.2019.006. PubMed DOI

Lodi R, et al. Deficient energy metabolism is associated with low free magnesium in the brains of patients with migraine and cluster headache. Brain Res. Bull. 2001;54:437–441. doi: 10.1016/S0361-9230(01)00440-3. PubMed DOI

Harper DG, et al. Energetic and cell membrane metabolic products in patients with primary insomnia: A 31-phosphorus magnetic resonance spectroscopy study at 4 tesla. Sleep. 2013;36:493–500. doi: 10.5665/sleep.2530. PubMed DOI PMC

Liu Y, Gu Y, Yu X. Assessing tissue metabolism by phosphorous-31 magnetic resonance spectroscopy and imaging: A methodology review. Quant. Imaging Med. Surg. 2017;7:707–726. doi: 10.21037/qims.2017.11.03. PubMed DOI PMC

Fukuda Y, et al. Superparamagnetic iron oxide (SPIO) MRI contrast agent for bone marrow imaging: Differentiating bone metastasis and osteomyelitis. Magn. Reson. Med. Sci. 2006;5:191–196. doi: 10.2463/mrms.5.191. PubMed DOI

Lu J, et al. Manganese ferrite nanoparticle micellar nanocomposites as MRI contrast agent for liver imaging. Biomaterials. 2009;30:2919–2928. doi: 10.1016/j.biomaterials.2009.02.001. PubMed DOI

Pechrova, Z., Lobaz, V., Konefał, M., Konefał, R. & Hruby, M. Colloidal probe based on iron(III)-doped calcium phytate nanoparticles for 31P NMR monitoring of bacterial siderophores. Colloids Interface Sci. Commun.42, 100427 (2021).

Boehm-Sturm P, et al. Low-molecular-weight iron chelates may be an alternative to gadolinium-based contrast agents for T1-weighted contrast-enhanced MR imaging. Radiology. 2018;286:537–546. doi: 10.1148/radiol.2017170116. PubMed DOI

Liu, G. et al. Black phosphorus nanosheets-based stable drug delivery system via drug-self-stabilization for combined photothermal and chemo cancer therapy. Chem. Eng. J.375, 121917 (2019).

Monge S, Canniccioni B, Graillot A, Robin J-J. Phosphorus-containing polymers: A great opportunity for the biomedical field. Biomacromol. 2011;12:1973–1982. doi: 10.1021/bm2004803. PubMed DOI

Oatway L, Vasanthan T, Helm JH. Phytic acid. Food Rev. Int. 2001;17:419–431. doi: 10.1081/FRI-100108531. DOI

Harland BF, Morris ER. Phytate: A good or a bad food component? Nutr. Res. 1995;15:733–754. doi: 10.1016/0271-5317(95)00040-P. DOI

Iimura, T., Fukushima, Y., Kumita, S., Ogawa, R. & Hyakusoku, H. Estimating lymphodynamic conditions and lymphovenous anastomosis efficacy using (99m)Tc-phytate lymphoscintigraphy with SPECT-CT in patients with lower-limb lymphedema. Plast. Reconstr. Surg. Glob. Open3, e404 (2015). PubMed PMC

Graf, E. & Eaton, J. W. Dietary suppression of colonic cancer. Fiber or phytate? Cancer56, 717–718 (1985). PubMed

Nielsen AVF, Tetens I, Meyer AS. Potential of phytase-mediated iron release from cereal-based foods: A quantitative view. Nutrients. 2013;5:3074–3098. doi: 10.3390/nu5083074. PubMed DOI PMC

Holden VI, Bachman MA. Diverging roles of bacterial siderophores during infection. Metallomics. 2015;7:986–995. doi: 10.1039/C4MT00333K. PubMed DOI

Hider, R. C. Siderophore mediated absorption of iron. in Siderophores from Microorganisms and Plants 25–87 (Springer Berlin Heidelberg, 2007).

Miethke M, Marahiel MA. Siderophore-based iron acquisition and pathogen control. Microbiol. Mol. Biol. Rev. 2007;71:413–451. doi: 10.1128/MMBR.00012-07. PubMed DOI PMC

Neilands JB. Siderophores: structure and function of microbial iron transport compounds. J. Biol. Chem. 1995;270:26723–26726. doi: 10.1074/jbc.270.45.26723. PubMed DOI

Wang Y, Liu Z, Lin T-M, Chanana S, Xiong MP. Nanogel-DFO conjugates as a model to investigate pharmacokinetics, biodistribution, and iron chelation in vivo. Int. J. Pharm. 2018;538:79–86. doi: 10.1016/j.ijpharm.2018.01.004. PubMed DOI PMC

Ellermann M, Arthur JC. Siderophore-mediated iron acquisition and modulation of host-bacterial interactions. Free Radic. Biol. Med. 2017;105:68–78. doi: 10.1016/j.freeradbiomed.2016.10.489. PubMed DOI PMC

Wilson BR, Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Siderophores in iron metabolism: From mechanism to therapy potential. Trends Mol. Med. 2016;22:1077–1090. doi: 10.1016/j.molmed.2016.10.005. PubMed DOI PMC

Yilmaz, B. & Li, H. Gut Microbiota and iron: The crucial actors in health and disease. Pharmaceuticals (Basel)11, 98 (2018). PubMed PMC

Khan A, Singh P, Srivastava A. Synthesis, nature and utility of universal iron chelator—Siderophore: A review. Microbiol. Res. 2017;212–213:103–111. PubMed

Zheng T, Bullock JL, Nolan EM. Siderophore-mediated cargo delivery to the cytoplasm of Escherichia coli and Pseudomonas aeruginosa: syntheses of monofunctionalized enterobactin scaffolds and evaluation of enterobactin-cargo conjugate uptake. J. Am. Chem. Soc. 2012;134:18388–18400. doi: 10.1021/ja3077268. PubMed DOI

Zhang, Z., Cheng, W., Pan, Y., & Jia, L. Anticancer agent-loaded PLGA nanomedicine with smart response and targeted delivery for the treatment of lung cancer. J. Mater. Chem. B.4, (2020). PubMed

Pohaku MK, K., Liberman, A., Kummel, A. C., Trogler, W. C. Iron(III)-Doped, Silica Nanoshells: A Biodegradable Form of Silica. J. Am. Chem. Soc. 2012;134(34):13997–14003. doi: 10.1021/ja3036114. PubMed DOI PMC

Wang Y-XJ. Superparamagnetic iron oxide based MRI contrast agents: Current status of clinical application. Quant. Imaging Med. Surg. 2011;1:35–40. PubMed PMC

Knobloch, G. et al. Relaxivity of Ferumoxytol at 1.5 T and 3.0 T. Investig. radiol.53(5), 257–263 (2018). PubMed PMC

Kamp DW, et al. Phytic acid, an iron chelator, attenuates pulmonary inflammation and fibrosis in rats after intratracheal instillation of asbestos. Toxicol. Pathol. 1995;23:689–695. doi: 10.1177/019262339502300606. PubMed DOI

Soldin OP, et al. Serum iron, ferritin, transferrin, total iron binding capacity, hs-CRP, LDL cholesterol and magnesium in children; new reference intervals using the Dade Dimension Clinical Chemistry System. Clin. Chim. Acta. 2004;342:211–217. doi: 10.1016/j.cccn.2004.01.002. PubMed DOI PMC

Jirak D, Janacek J. Volume of the crocodilian brain and endocast during ontogeny. PLoS ONE. 2017;12:e0178491. doi: 10.1371/journal.pone.0178491. PubMed DOI PMC

Cationic fluorinated micelles for cell labeling and 19F-MR imaging

Long-term in vivo dissolution of thermo- and pH-responsive, 19F magnetic resonance-traceable and injectable polymer implants

Iron-based compounds coordinated with phospho-polymers as biocompatible probes for dual 31P/1H magnetic resonance imaging and spectroscopy

Phosphorus-Containing Polymers as Sensitive Biocompatible Probes for 31P Magnetic Resonance