Systematic Review

A Comprehensive Review of Physicochemical Properties Influencing the Magnetic Behavior and Relaxivity of Nanoparticle-Based MRI Contrast Agents

Abstract

Purpose: This review aimed to comprehensively assess how various physicochemical properties of nanoparticle-based MRI contrast agents—such as size, concentration, surface coating, charge, pH-responsiveness, and surface functionalization—affect their magnetic behavior and relaxivity. Moreover, this study evaluated the synergistic effects of these parameters to provide an integrated understanding of their combined impact on imaging performance.
Materials and Methods: A systematic search was conducted across PubMed, Scopus, Web of Science, and IEEE Xplore for studies published between 2015 and 2025. Search terms included combinations of “MRI contrast agents,” “nanoparticles,” “particle size,” “surface coating,” “surface charge,” “polymer type,” “relaxivity,” “drug delivery,” and “circulation time.” The search strategy used Boolean operators (AND, OR), Medical Subject Headings (MeSH), and filters for English-language, peer-reviewed, experimental articles. Inclusion criteria focused on original studies assessing how size, surface characteristics (charge, polymer, pH responsiveness), and concentration affect MRI relaxivity and imaging performance. Data were extracted and synthesized to evaluate trends, thresholds, and correlations among parameters.
Results: The review identified that nanoparticle size below 20 nm significantly enhances T₁ relaxivity, while concentrations above 0.5 mg/mL often lead to signal quenching and increased cytotoxicity. Surface coatings such as PEG and silica were found to improve biocompatibility and alter magnetic response depending on thickness and binding chemistry. Notably, the synergistic effects among these parameters were highlighted, demonstrating that optimized combinations of size, concentration, and surface coating could significantly enhance magnetic behavior and relaxivity, offering a more accurate and efficient MRI performance. This review identified threshold values for key nanoparticle properties—such as size, concentration, and surface coating—that significantly influence MRI relaxivity and imaging performance, providing a clear understanding of their combined effects.
Conclusion: This review highlights that optimizing the design of nanoparticle-based MRI contrast agents requires a synergistic approach, where key parameters—size, concentration, surface coating, and surface functionalization—are co-engineered to enhance magnetic behavior and relaxivity. Specifically, maintaining particle sizes below 20 nm, using biocompatible coatings like PEG or silica, and optimizing concentration between 0.1–0.5 mg/mL were identified as critical factors. This integrated framework provides a guideline for developing next-generation contrast agents with superior imaging performance and minimal toxicity.

1- Jing Huang et al., "Casein-Coated Iron Oxide Nanoparticles for High MRI Contrast Enhancement and Efficient Cell Targeting." ACS applied materials & interfaces, Vol. 504/30 (2013).
2- Guoming Huang et al., "Tunable T-1 and T-2 contrast abilities of manganese-engineered iron oxide nanoparticles through size control." Nanoscale, Vol. 607/31 (2014).
3- Z. Y. Chen et al., "Advance of molecular imaging technology and targeted imaging agent in imaging and therapy." (in eng), Biomed Res Int, Vol. 2014p. 819324, (2014).
4- Carlos Martínez-Boubeta et al., "Learning from Nature to Improve the Heat Generation of Iron-Oxide Nanoparticles for Magnetic Hyperthermia Applications." Scientific reports, Vol. 3p. 1652, 04/11 (2013).
5- Azmi Aulia Rahmani, Qi Jia, Husein H. Bahti, Retna Putri Fauzia, and Santhy Wyantuti, "Recent advances in lanthanide-based nanoparticle contrast agents for magnetic resonance imaging: Synthesis, characterization, and applications." OpenNano, Vol. 21p. 100226, 2025/01/01/ (2025).
6- J. Wahsner, E. M. Gale, A. Rodríguez-Rodríguez, and P. Caravan, "Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers." (in eng), Chem Rev, Vol. 119 (No. 2), pp. 957-1057, Jan 23 (2019).
7- D. Lau, P. G. Corrie, and F. A. Gallagher, "MRI techniques for immunotherapy monitoring." (in eng), J Immunother Cancer, Vol. 10 (No. 9), Sep (2022).
8- J. Bonlawar et al., "Targeted Nanotheransotics: Integration of Preclinical MRI and CT in the Molecular Imaging and Therapy of Advanced Diseases." (in eng), Nanotheranostics, Vol. 8 (No. 3), pp. 401-26, (2024).
9- F. Garello et al., "MRI detection of free-contrast agent nanoparticles." (in eng), Magn Reson Med, Vol. 93 (No. 2), pp. 761-74, Feb (2025).
10- C. Jacinto et al., "Nanoparticles based image-guided thermal therapy and temperature feedback." (in eng), J Mater Chem B, Vol. 13 (No. 1), pp. 54-102, Dec 18 (2024).
11- N. Brown et al., "Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification." (in eng), Theranostics, Vol. 13 (No. 14), pp. 4711-29, (2023).
12- Seraj Mohaghegh, Tarighatnia Ali, Omidi Yadollah, Barar Jaleh, Aghanejad Ayuob, and Khosro and Adibkia, "Multifunctional magnetic nanoparticles for MRI-guided co-delivery of erlotinib and L-asparaginase to ovarian cancer." Journal of Microencapsulation, Vol. 39 (No. 4), pp. 394-408, 2022/05/19 (2022).
13- Fakhrosadat Sajjadian Ramin Ghasemi Shayan, "Sensitivity and Specificity Improvement for Breast Cancer Detection by Tumor-Microenvironment Multimodality Molecular Imaging." Mathews J Case Rep., Vol. 8 (No. 10), p. 130, (2023).
14- Ramin Ghasemi Shayan, Tohid Mortezazadeh, and Mehdi Khalilnejad, "Article Acceptance Certificate Title: Application of Manganese Oxide (MnO) Nanoparticles in Multimodal Molecular Imaging and Cancer Therapy: A Review." Nanomedicine, Vol. 805/26 (2021).
15- Ramin Ghasemi Shayan, "Comprehensive Management of Prostate Cancer: From Diagnosis to Survivorship Post-radiotherapy." Oncology Advances, (No. 000), (2024).
16- Tarighatnia Ali, Mahmoudi Golshan, Kiani Mahnaz, and Nader Nader, "Current Challenges and New Opportunities of Hybrid Nanoparticles for Diagnosis and Treatment of Cancer." Frontiers in Biomedical Technologies, Vol. 11 (No. 1), 01/01 (2024).
17- T. Tegafaw et al., "Magnetic Nanoparticle-Based High-Performance Positive and Negative Magnetic Resonance Imaging Contrast Agents." (in eng), Pharmaceutics, Vol. 15 (No. 6), Jun 15 (2023).
18- J. Pellico, C. M. Ellis, and J. J. Davis, "Nanoparticle-Based Paramagnetic Contrast Agents for Magnetic Resonance Imaging." (in eng), Contrast Media Mol Imaging, Vol. 2019p. 1845637, (2019).
19- Ruth Antwi-Baah, Yajing Wang, Xiaoqin Chen, and Kui Yu, "Metal-Based Nanoparticle Magnetic Resonance Imaging Contrast Agents: Classifications, Issues, and Countermeasures toward their Clinical Translation." Advanced Materials Interfaces, Vol. 9 (No. 9), p. 2101710, (2022).
20- M. Habeeb, H. T. Vengateswaran, A. K. Tripathi, S. T. Kumbhar, H. W. You, and Hariyadi, "Enhancing biomedical imaging: the role of nanoparticle-based contrast agents." (in eng), Biomed Microdevices, Vol. 26 (No. 4), p. 42, Oct 23 (2024).
21- D. Zhang, J. Zhang, X. Bian, P. Zhang, W. Wu, and X. Zuo, "Iron Oxide Nanoparticle-Based T(1) Contrast Agents for Magnetic Resonance Imaging: A Review." (in eng), Nanomaterials (Basel), Vol. 15 (No. 1), Dec 28 (2024).
22- W. Wang, X. Liu, X. Li, B. Geng, and E. Zhao, "Application of MRI imaging technology based on magnetic nanoparticles in diagnosis and prognosis evaluation of prostate cancer." (in eng), SLAS Technol, Vol. 29 (No. 6), p. 100225, Dec (2024).
23- A. Mali, E. L. Kaijzel, H. J. Lamb, and L. J. Cruz, "(19)F-nanoparticles: Platform for in vivo delivery of fluorinated biomaterials for (19)F-MRI." (in eng), J Control Release, Vol. 338pp. 870-89, Oct 10 (2021).
24- F. Mao and J. Zhou, "A needs analysis of ESP courses in colleges of art and design: Consensus and divergence." (in eng), PLoS One, Vol. 19 (No. 6), p. e0305210, (2024).
25- Zheyu Shen et al., "Multifunctional Theranostic Nanoparticles Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1-Weighted Magnetic Resonance Imaging and Chemotherapy." ACS Nano, Vol. 11 (No. 11), pp. 10992-1004, (2017).
26- A. Amraee et al., "Evaluation of ultra-small iron oxide nanoparticles as T1-weighted MRI contrast in cancerous tissues: a meta-analysis." Clinical and Translational Imaging, Vol. 10 (No. 4), pp. 403-11, 2022/08/01 (2022).
27- L. Zhu, H. Mao, and L. Yang, "Advanced iron oxide nanotheranostics for multimodal and precision treatment of pancreatic ductal adenocarcinoma." (in eng), Wiley Interdiscip Rev Nanomed Nanobiotechnol, Vol. 14 (No. 4), p. e1793, Jul (2022).
28- O. A. Kuchur, S. A. Tsymbal, M. V. Shestovskaya, N. S. Serov, M. S. Dukhinova, and A. A. Shtil, "Metal-derived nanoparticles in tumor theranostics: Potential and limitations." (in eng), J Inorg Biochem, Vol. 209p. 111117, Aug (2020).
29- Z. Shi, P. Wang, L. Xie, and X. Zhao, "Biocompatible Au-Fe3O4 Nanoparticle-based Magnetic Resonance Imaging in the Diagnosis of Liver Tumor." (in eng), Cell Mol Biol (Noisy-le-grand), Vol. 68 (No. 3), pp. 59-66, Mar 31 (2022).
30- K. J. Chen et al., "A small MRI contrast agent library of gadolinium(III)-encapsulated supramolecular nanoparticles for improved relaxivity and sensitivity." (in eng), Biomaterials, Vol. 32 (No. 8), pp. 2160-5, Mar (2011).
31- Y. Jiang et al., "Relaxivity Enhancement of Hybrid Micelles via Modulation of Water Coordination Numbers for Magnetic Resonance Lymphography." (in eng), Nano Lett, Vol. 23 (No. 18), pp. 8505-14, Sep 27 (2023).
32- Y. You et al., "Nanoparticle-enhanced synergistic HIFU ablation and transarterial chemoembolization for efficient cancer therapy." (in eng), Nanoscale, Vol. 8 (No. 7), pp. 4324-39, Feb 21 (2016).
33- Y. R. Zheng, Y. K. Chen, S. H. Lin, H. Cao, and Q. Chen, "Effect of High-Frequency Oscillatory Ventilation, Combined With Prone Positioning, in Infants With Acute Respiratory Distress Syndrome After Congenital Heart Surgery: A Prospective Randomized Controlled Trial." (in eng), J Cardiothorac Vasc Anesth, Vol. 36 (No. 10), pp. 3847-54, Oct (2022).
34- X. Mao, J. Xu, and H. Cui, "Functional nanoparticles for magnetic resonance imaging." (in eng), Wiley Interdiscip Rev Nanomed Nanobiotechnol, Vol. 8 (No. 6), pp. 814-41, Nov (2016).
35- M. Y. Ahmad et al., "Functionalized Lanthanide Oxide Nanoparticles for Tumor Targeting, Medical Imaging, and Therapy." (in eng), Pharmaceutics, Vol. 13 (No. 11), Nov 8 (2021).
36- D. P. Seiter et al., "Ferumoxytol dynamic contrast enhanced magnetic resonance imaging identifies altered placental cotyledon perfusion in rhesus macaques†." (in eng), Biol Reprod, Vol. 107 (No. 6), pp. 1517-27, Dec 10 (2022).
37- X. Dong et al., "Magnetic resonance colonography with intestine-absorbable nanoparticle contrast agents in evaluation of colorectal inflammation." (in eng), Eur Radiol, Vol. 31 (No. 7), pp. 4615-24, Jul (2021).
38- S. Herz et al., "Magnetic Particle Imaging Guided Real-Time Percutaneous Transluminal Angioplasty in a Phantom Model." (in eng), Cardiovasc Intervent Radiol, Vol. 41 (No. 7), pp. 1100-05, Jul (2018).
39- K. Szigeti et al., "Thallium Labeled Citrate-Coated Prussian Blue Nanoparticles as Potential Imaging Agent." (in eng), Contrast Media Mol Imaging, Vol. 2018p. 2023604, (2018).
40- Leon Smith, Hilary L. Byrne, David Waddington, and Zdenka Kuncic, "Nanoparticles for MRI-guided radiation therapy: a review." Cancer Nanotechnology, Vol. 13 (No. 1), p. 38, 2022/11/12 (2022).
41- T. Mortezazadeh 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." (in eng), Magma, Vol. 32 (No. 4), pp. 487-500, Aug (2019).
42- K. Cheng, M. Yang, R. Zhang, C. Qin, X. Su, and Z. Cheng, "Hybrid nanotrimers for dual T1 and T2-weighted magnetic resonance imaging." (in eng), ACS Nano, Vol. 8 (No. 10), pp. 9884-96, Oct 28 (2014).
43- H. Seo et al., "A DNA-Based MRI Contrast Agent for Quantitative pH Measurement." (in eng), ACS Sens, Vol. 6 (No. 3), pp. 727-32, Mar 26 (2021).
44- Amir Kazemi et al., "Polydopamine-Coated Zn-MOF-74 Nanocarriers: Versatile Drug Delivery Systems with Enhanced Biocompatibility and Cancer Therapeutic Efficacy." Journal of Inorganic and Organometallic Polymers and Materials, Vol. 34 (No. 12), pp. 5718-31, 2024/12/01 (2024).
45- C. Sun, R. Sze, and M. Zhang, "Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MRI." (in eng), J Biomed Mater Res A, Vol. 78 (No. 3), pp. 550-7, Sep 1 (2006).
46- D. Patel, A. Kell, B. Simard, B. Xiang, H. Y. Lin, and G. Tian, "The cell labeling efficacy, cytotoxicity and relaxivity of copper-activated MRI/PET imaging contrast agents." (in eng), Biomaterials, Vol. 32 (No. 4), pp. 1167-76, Feb (2011).
47- C. Nwasike, E. Purr, E. Yoo, J. S. Nagi, and A. L. Doiron, "Activatable Nanoparticles: Recent Advances in Redox-Sensitive Magnetic Resonance Contrast Agent Candidates Capable of Detecting Inflammation." (in eng), Pharmaceuticals (Basel), Vol. 14 (No. 1), Jan 16 (2021).
48- R. Bilardo, F. Traldi, A. Vdovchenko, and M. Resmini, "Influence of surface chemistry and morphology of nanoparticles on protein corona formation." (in eng), Wiley Interdiscip Rev Nanomed Nanobiotechnol, Vol. 14 (No. 4), p. e1788, Jul (2022).
49- Y. Nakamura, A. Mochida, P. L. Choyke, and H. Kobayashi, "Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer?" (in eng), Bioconjug Chem, Vol. 27 (No. 10), pp. 2225-38, Oct 19 (2016).
50- V. C. Deivayanai et al., "A comprehensive review on advances in nanoparticle-mediated cancer therapeutics: Current research and future perspectives." Cancer Pathogenesis and Therapy, 2024/12/09/ (2024).
51- S. Surasinghe, I. Liatsou, Z. Nováková, C. Bařinka, D. Artemov, and S. Hapuarachchige, "Optical and MRI-Guided Theranostic Application of Ultrasmall Superparamagnetic Iron Oxide Nanodrug Conjugate for PSMA-Positive Prostate Cancer Therapy." (in eng), ACS Appl Mater Interfaces, Vol. 17 (No. 8), pp. 11611-23, Feb 26 (2025).
52- N. M. Ariyasingha et al., "Developing Hyperpolarized Butane Gas for Ventilation Lung Imaging." (in eng), Chem Biomed Imaging, Vol. 2 (No. 10), pp. 698-710, Oct 28 (2024).
53- K. Y. Kim and K. A. Chang, "Therapeutic Potential of Magnetic Nanoparticle-Based Human Adipose-Derived Stem Cells in a Mouse Model of Parkinson's Disease." (in eng), Int J Mol Sci, Vol. 22 (No. 2), Jan 11 (2021).
54- J. S. Suk, Q. Xu, N. Kim, J. Hanes, and L. M. Ensign, "PEGylation as a strategy for improving nanoparticle-based drug and gene delivery." (in eng), Adv Drug Deliv Rev, Vol. 99 (No. Pt A), pp. 28-51, Apr 1 (2016).
55- N. Hoshyar, S. Gray, H. Han, and G. Bao, "The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction." (in eng), Nanomedicine (Lond), Vol. 11 (No. 6), pp. 673-92, Mar (2016).
56- J. S. Ni, Y. Li, W. Yue, B. Liu, and K. Li, "Nanoparticle-based Cell Trackers for Biomedical Applications." (in eng), Theranostics, Vol. 10 (No. 4), pp. 1923-47, (2020).
57- T. R. Kyriakides et al., "Biocompatibility of nanomaterials and their immunological properties." (in eng), Biomed Mater, Vol. 16 (No. 4), Mar 11 (2021).
58- Z. Amoozgar and Y. Yeo, "Recent advances in stealth coating of nanoparticle drug delivery systems." (in eng), Wiley Interdiscip Rev Nanomed Nanobiotechnol, Vol. 4 (No. 2), pp. 219-33, Mar-Apr (2012).
59- D. T. Savage, J. Z. Hilt, and T. D. Dziubla, "In Vitro Methods for Assessing Nanoparticle Toxicity." (in eng), Methods Mol Biol, Vol. 1894pp. 1-29, (2019).
60- M. Bellusci et al., "Biodistribution and acute toxicity of a nanofluid containing manganese iron oxide nanoparticles produced by a mechanochemical process." (in eng), Int J Nanomedicine, Vol. 9pp. 1919-29, (2014).
61- E. Roy, S. Patra, R. Madhuri, and P. K. Sharma, "Stimuli-responsive poly(N-isopropyl acrylamide)-co-tyrosine@gadolinium: Iron oxide nanoparticle-based nanotheranostic for cancer diagnosis and treatment." (in eng), Colloids Surf B Biointerfaces, Vol. 142pp. 248-58, Jun 1 (2016).
62- P. J. Hoopes et al., "Imaging and modification of the tumor vascular barrier for improvement in magnetic nanoparticle uptake and hyperthermia treatment efficacy." (in eng), Proc SPIE Int Soc Opt Eng, Vol. 8584Feb 26 (2013).
63- G. Liang et al., "Label-free, nucleotide-mediated dispersion of magnetic nanoparticles for "non-sandwich type" MRI-based quantification of enzyme." (in eng), Biosens Bioelectron, Vol. 41pp. 78-83, Mar 15 (2013).
64- Benedict You Wei Hsu et al., "A Hybrid Silica Nanoreactor Framework for Encapsulation of Hollow Manganese Oxide Nanoparticles of Superior T1 Magnetic Resonance Relaxivity." Advanced Functional Materials, Vol. 25 (No. 33), pp. 5269-76, 2015/09/01 (2015).
65- Y. Sun et al., "Metal-Organic Framework Nanocarriers for Drug Delivery in Biomedical Applications." (in eng), Nanomicro Lett, Vol. 12 (No. 1), p. 103, May 2 (2020).
66- R. Wei et al., "Iron-oxide-based twin nanoplates with strong T(2) relaxation shortening for contrast-enhanced magnetic resonance imaging." (in eng), Nanoscale, Vol. 10 (No. 38), pp. 18398-406, Oct 4 (2018).
67- S. K. Golombek et al., "Tumor targeting via EPR: Strategies to enhance patient responses." (in eng), Adv Drug Deliv Rev, Vol. 130pp. 17-38, May (2018).
68- S. Barua and S. Mitragotri, "Challenges associated with Penetration of Nanoparticles across Cell and Tissue Barriers: A Review of Current Status and Future Prospects." (in eng), Nano Today, Vol. 9 (No. 2), pp. 223-43, Apr 1 (2014).
69- T. Yang et al., ""Targeting Design" of Nanoparticles in Tumor Therapy." (in eng), Pharmaceutics, Vol. 14 (No. 9), Sep 11 (2022).
70- H. Lee et al., "Silica nanoparticle-based dual imaging colloidal hybrids: cancer cell imaging and biodistribution." (in eng), Int J Nanomedicine, Vol. 10 Spec Iss (No. Spec Iss), pp. 215-25, (2015).
71- Maryam Razaghi, Ali Ramazani, Mehdi Khoobi, Tohid Mortezazadeh, Eda Ayşe Aksoy, and Tuba Tüylü Küçükkılınç, "Highly fluorinated graphene oxide nanosheets for anticancer linoleic-curcumin conjugate delivery and T2-Weighted magnetic resonance imaging: In vitro and in vivo studies." Journal of Drug Delivery Science and Technology, Vol. 60p. 101967, 2020/12/01/ (2020).
72- J. Fang et al., "Manipulating the surface coating of ultra-small Gd2O3 nanoparticles for improved T1-weighted MR imaging." (in eng), Biomaterials, Vol. 35 (No. 5), pp. 1636-42, Feb (2014).
73- Y. Li, W. Long, H. Zhou, T. Tan, and H. Xie, "Revolutionizing breast cancer Ki-67 diagnosis: ultrasound radiomics and fully connected neural networks (FCNN) combination method." (in eng), Breast Cancer Res Treat, Vol. 207 (No. 2), pp. 453-68, Sep (2024).
74- Tarighatnia Ali, Johal Gurkaran, Aghanejad Ayuob, Ghadiri Hossein, and Nader Nader, "Tips and Tricks in Molecular Imaging: A practical Approach." Frontiers in Biomedical Technologies, Vol. 8 (No. 3), 09/01 (2021).
75- Azadeh Amraee, Abolfazl Sarikhani, Leili Darvish, Zahra Alamzadeh, Rasoul Irajirad, and Seyed Rabie Mahdavi, "Curcumin Coated Ultra-Small Iron Oxide Nanoparticles as T1 Contrast Agents for Magnetic Resonance Imaging of Cancer Cells." Journal of Biomedical Physics and Engineering, Vol. 14 (No. 5), pp. 447-56, (2024).
76- Nasim Jamshidi, Ali Tarighatnia, Mona Ghaziyani, Fakhrossadat Sajadian, Maryam Olad-Ghaffari, and Nader Nader, Folic Acid-Conjugated Fe-Au-Based Nanoparticles for Dual Detection of Breast Cancer Cells by Magnetic Resonance Imaging and Computed Tomography. (2023).
77- M. A. Pysz, S. S. Gambhir, and J. K. Willmann, "Molecular imaging: current status and emerging strategies." Clinical Radiology, Vol. 65 (No. 7), pp. 500-16, 2010/07/01/ (2010).
Files
IssueVol 12 No 4 (2025) QRcode
SectionSystematic Review(s)
DOI https://doi.org/10.18502/fbt.v12i4.19828
Keywords
Nanoparticle Magnetic Resonance Imaging Contrast Agents Particle Size Surface Charge Surface Coating Polymer Type pH-Responsive Release Concentration Relaxivity Drug Delivery Blood Circulation Time Targeted Imaging

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Malekzadeh R, Ghasemi Shayan R, Jangjoo AG, Khani M, Soleimani S, Pourfarshid A, Mortezazadeh T, Molazadeh M. A Comprehensive Review of Physicochemical Properties Influencing the Magnetic Behavior and Relaxivity of Nanoparticle-Based MRI Contrast Agents. Frontiers Biomed Technol. 2025;12(4):918-940.