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Review Open Access

Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review)

  • Authors:
    • Taoming Du
    • Haiyang Luo
    • Huizhen Song
    • Tao Lin
    • Qin Yu
  • View Affiliations / Copyright

    Affiliations: Department of Radiology, Chengdu Seventh People's Hospital (Affiliated Cancer Hospital of Chengdu Medical College), Chengdu, Sichuan 610213, P.R. China
    Copyright: © Du et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 70
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    Published online on: July 15, 2025
       https://doi.org/10.3892/ijo.2025.5776
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Abstract

Magnetic Resonance Imaging (MRI) relies on contrast agents to enhance image quality and diagnostic accuracy. Traditional metal‑based agents, such as gadolinium compounds, raise safety concerns due to potential toxicity and long‑term retention in the body. The present review examines recent advancements in non‑metal‑based MRI contrast agents, focusing on fluorine‑19 (19F) compounds, chemical exchange saturation transfer (CEST) agents, nitroxide radicals, and hyperpolarized carbon agents. It discussed the mechanisms by which these agents improve contrast, including their biocompatibility and ability to provide molecular and metabolic information. Key findings highlight the high specificity of19F agents due to negligible background signals, the capacity of CEST agents for molecular imaging without metals, nitroxide radicals' utility in redox‑sensitive imaging, and hyperpolarized 13C compounds' role in real‑time metabolic assessment. Despite challenges such as low sensitivity and technical complexities, these non‑metal‑based agents offer promising, safer alternatives with enhanced diagnostic capabilities, paving the way for more precise and personalized medical imaging.
View Figures

Figure 1

Illustration of aiMRI. (A) RT-induced
acute inflammatory response leads to ROS production, which exerts
tumor inhibition through ROS-induced cell apoptosis and T-cell
activation pathways. The adaptive immune responses usually take
days to weeks after RT. The aiMRI is applied to quantify the ROS at
an early time (24-48 h) after RT, which is to stratify the tumor
inhibition. (B) The procedure of self-assembly and disassembly of
the aiMRI nanoprobe that is composed of IO NPs, Gd species, and
triblock PEG-PPS-PEG-NH2 polymers, denoted as IO-Gd NVs. The
oxidation of hydrophobic thioethers to hydrophilic sulfones leads
to swelling of the polymers and decomposition of the IO-Gd NVs.
This procedure confers dual-positive factors to the T1 MRI off-on
effect: i) the quencher's T2 effect is decreased upon disassembly
due to the dispersed magnetic field coupling effect; ii) the Q-E
distance is increased due to the oxidation-induced swelling of
polymers equipped with Gd species. RT, radiotherapy; ROS, reactive
oxygen species; aiMRI, activatable inflammation magnetic resonance
imaging; IO NPs, iron oxide nanoparticles; Gd, gadolinium; T1,
longitudinal relaxation time; T2, transverse relaxation time; NVs
PEG-PPS-PEG-NH2 (a triblock polymer); Q-E quencher-enhancer; DC,
dendritic cells.

Figure 2

Detection of in vivo pH
changes and ORTW and RT outcomes in NSCLC xenograft tumor model.
(A) shows typical T1-weighted imaging, fluorine/proton chemical
exchange saturation transfer MRI, and chemical shift imaging
outcomes after administering Gly-PFOBs. (B) Statistical outcomes
for 19F/1H-CESTMR signal intensities.
**P<0.01 (P=0.0067), not significant. CEST and BOLD
MR imaging of BALB/c nude mice bearing NCI-H460 lung xenografts
following the intratumoral administration of (C) oxygen-enhanced
Gly-PFOBs(O2) or (D) PFOBs(O2) over a period.
(E) Changes in the dynamic CEST MR signal in the tumor area
post-injection of Gly-PFOBs(O2) or PFOBs(O2).
**P<0.01 (P=0.0030); Gly-PFOBs (O2) vs.
PFOBs (O2) (69).
ORTW, optimize the radiotherapy time window; RT, Radiotherapy;
NSCLC, non-small cell lung cancer; T1, longitudinal relaxation
time; MRI, magnetic resonance imaging; PFOB, perfluorooctyl
bromide; 19F, fluorine-19; CEST, chemical exchange saturation
transfer.

Figure 3

T1 MR imaging of Linear
pDHPMA-mPEG-Ppa-PROXYL in tumor bearing mice. (A) The chemical
composition and the degree of nitroxide incorporation in Linear
pDHPMA-mPEG-Ppa-PROXYL. (B) MR T1 imaging and peak enhancement in
tumor (red circle dashed lines), liver (red box dashed lines),
bladder (buff circle dashed lines), kidney (yellow circle dashed
lines) following the administration of Linear
pDHPMA-mPEG-Ppa-PROXYL. T1, longitudinal relaxation time; MR,
magnetic resonance; Linear pDHPMA-mPEG-Ppa-PROXYL, a water-soluble
biodegradable nitroxides-based macromolecular contrast agent.

Figure 4

T1 MR imaging of cross linked and
linear PCE mPEG Ppa PROXYL in tumor bearing mice. (A) Depiction of
linear and (B) networked PCE-mPEG-Ppa-PROXYL. T1 mapping imaging of
liver following administration of (C) networked and (D) linear
PCE-mPEG-Ppa-PROXYL. Significant improvement in liver imaging was
observed after 25 min, whereas in the group treated with linear
PCE-mPEG-Ppa-PROXYL, liver imaging enhancement was noted after 15
min, albeit with comparatively faint blue signals. The related T1
values were mapped across the liver following the administration of
(E) cross-linked and (F) linear PCE-mPEG-Ppa-PROXYL over various
time periods. (G) The inverse T1 relaxation times for the two liver
groups underwent quantitative analysis. T1, longitudinal relaxation
time; MR, magnetic resonance; PCE-mPEG-Ppa-PROXYL, a water-soluble
biodegradable nitroxides-based macromolecular contrast agent.

Figure 5

Non-metallic MR CAs G3-Tyr-PROXYL-ONa
radical dendrimer for glioblastoma diagnosis. (A) Structure of the
G3-Tyr-PROXYL-ONa radical dendrimer. (B) Top: Color-code scale for
RCE (Gd 0.1 and 0.04 mmol/kg, 30 min; and G3 radical dendrimer
0.025 mmol/kg, 60 min). Bottom: ROI kinetics for these agents,
showing the slower washout of G3. The maximum RCE calculated was
158% for Gd 0.1 mmol/kg, 113% for Gd 0.04 mmol/kg, and 126% for G3
0.025 mmol/kg. Contralateral enhancement was reproducible in all
cases (102±3%). Please note that 0.04 mmol/kg administration data
comes from retrospective cases administered with Gd-DOTA instead of
Gd-DTPA. Analyses were performed with the DCE@urLAB software
package. (C) Schematic representation of the ROI selection (blue
circles) for analysis in T1-weighted MRI, indicating ipsilateral
ROIs where CA are injected (right) and contralateral ROIs (left).
T1-weighted MRI after ex vivo administration of (D) 5 nmol
of gadopentetate dimeglumine to each injection point and (E) 1.25
nmol of the G3 radical dendrimer at each injection point. MR,
magnetic resonance; Cas, contrast agents; G3-Tyr-PROXYL-ONa, a
non-metallic MR CAs based on radical dendrimer; ROI, region of
interest; T1, longitudinal relaxation time; MRI, magnetic resonance
imaging; CA, contrast agents; RCE, relative contrast enhancement;
Gd, gadolinium.
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Copy and paste a formatted citation
Spandidos Publications style
Du T, Luo H, Song H, Lin T and Yu Q: Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review). Int J Oncol 67: 70, 2025.
APA
Du, T., Luo, H., Song, H., Lin, T., & Yu, Q. (2025). Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review). International Journal of Oncology, 67, 70. https://doi.org/10.3892/ijo.2025.5776
MLA
Du, T., Luo, H., Song, H., Lin, T., Yu, Q."Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review)". International Journal of Oncology 67.2 (2025): 70.
Chicago
Du, T., Luo, H., Song, H., Lin, T., Yu, Q."Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review)". International Journal of Oncology 67, no. 2 (2025): 70. https://doi.org/10.3892/ijo.2025.5776
Copy and paste a formatted citation
x
Spandidos Publications style
Du T, Luo H, Song H, Lin T and Yu Q: Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review). Int J Oncol 67: 70, 2025.
APA
Du, T., Luo, H., Song, H., Lin, T., & Yu, Q. (2025). Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review). International Journal of Oncology, 67, 70. https://doi.org/10.3892/ijo.2025.5776
MLA
Du, T., Luo, H., Song, H., Lin, T., Yu, Q."Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review)". International Journal of Oncology 67.2 (2025): 70.
Chicago
Du, T., Luo, H., Song, H., Lin, T., Yu, Q."Novel non‑metal‑based contrast agents for MR imaging: Emerging approaches and clinical perspectives (Review)". International Journal of Oncology 67, no. 2 (2025): 70. https://doi.org/10.3892/ijo.2025.5776
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