{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T07:47:03Z","timestamp":1774424823150,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Foundation","award":["DMR-2144790"],"award-info":[{"award-number":["DMR-2144790"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The excellent biocompatibility and favorable physicochemical properties of iron oxide nanoparticles have made them attractive candidates for magnetic resonance imaging. However, it remains challenging to synthesize high-performance T1 contrast agents with controlled sizes and biocompatible coating materials. In this study, we demonstrate a simple and environmentally friendly approach for synthesizing ultra-small iron oxide nanoparticles using bovine serum albumin (BSA) as a template. Following synthesis, the iron oxide nanoparticles (Fe3O4) were oxidized to Fe2O3 via the addition of hydrogen peroxide, which resulted in enhanced T1-weighted magnetic resonance contrast. The use of BSA not only stabilized the nanoparticles but also enabled precise control over nanoparticle size by adjusting the Fe-to-BSA molar ratio. This method yielded highly uniform and crystalline ultra-small nanoparticles ranging from approximately 3.7 to 7.9 nm in diameter. The T1 contrast performance of the Fe2O3@BSA nanoparticles was evaluated at 3 T magnetic field. Among the synthesized samples, nanoparticles with sizes of 4.6 nm exhibited the strongest T1 contrast enhancement along with low r2\/r1 ratios. These features highlight their potential as promising alternatives to gadolinium-based contrast agents. In addition to their superior performance, this synthesis method is low-cost and non-toxic, making it suitable for scalable biomedical applications.<\/jats:p>","DOI":"10.3390\/biom16030478","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:07:06Z","timestamp":1774271226000},"page":"478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of BSA-Coated Iron Oxide Nanoparticles with Size Control for High-Performance T1 Contrast Agents in Magnetic Resonance Imaging"],"prefix":"10.3390","volume":"16","author":[{"given":"Bosede","family":"Kolawole","sequence":"first","affiliation":[{"name":"Department of Chemistry, Physics and Atmospheric Science, Jackson State University, Jackson, MS 39217, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Zheng","sequence":"additional","affiliation":[{"name":"Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9889-5089","authenticated-orcid":false,"given":"Dongmei","family":"Cao","sequence":"additional","affiliation":[{"name":"Advanced Microscopy and Analytical Core, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2962-7504","authenticated-orcid":false,"given":"Yongfeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Physics and Atmospheric Science, Jackson State University, Jackson, MS 39217, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/00000446-200212000-00012","article-title":"Magnetic resonance imaging","volume":"102","author":"Carr","year":"2002","journal-title":"Am. J. Nurs."},{"key":"ref_2","first-page":"65","article-title":"Magnetic resonance imaging (MRI)-A review","volume":"3","author":"Katti","year":"2011","journal-title":"Int. J. Dent. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1021\/acsnano.7b03075","article-title":"T1\u2013T2 Dual-Modal Magnetic Resonance Imaging: From Molecular Basis to Contrast Agents","volume":"11","author":"Zhou","year":"2017","journal-title":"ACS Nano"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1906539","DOI":"10.1002\/adma.201906539","article-title":"Iron Oxide Nanoparticles as T(1) Contrast Agents for Magnetic Resonance Imaging: Fundamentals, Challenges, Applications, and Prospectives","volume":"33","author":"Jeon","year":"2021","journal-title":"Adv. Mater."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1002\/anie.201308494","article-title":"Copper-64-alloyed gold nanoparticles for cancer imaging: Improved radiolabel stability and diagnostic accuracy","volume":"53","author":"Zhao","year":"2014","journal-title":"Angew. Chem. (Int. Ed. Engl.)"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e200102","DOI":"10.1148\/ryct.2020200102","article-title":"Gadolinium-based Contrast Agents for Cardiac MRI: Use of Linear and Macrocyclic Agents with Associated Safety Profile from 154,779 European Patients","volume":"2","author":"Uhlig","year":"2020","journal-title":"Radiol. Cardiothorac. Imaging"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.3892\/ijmm.2016.2744","article-title":"MRI contrast agents: Classification and application (Review)","volume":"38","author":"Xiao","year":"2016","journal-title":"Int. J. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"26764","DOI":"10.1039\/C8RA04530E","article-title":"Gadolinium-labelled iron\/iron oxide core\/shell nanoparticles as T1\u2013T2 contrast agent for magnetic resonance imaging","volume":"8","author":"Wang","year":"2018","journal-title":"RSC Adv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1021\/acs.chemrev.8b00363","article-title":"Chemistry of MRI Contrast Agents: Current Challenges and New Frontiers","volume":"119","author":"Wahsner","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100503","DOI":"10.1016\/j.ejro.2023.100503","article-title":"Gadolinium contrast agents- challenges and opportunities of a multidisciplinary approach: Literature review","volume":"11","author":"Iyad","year":"2023","journal-title":"Eur. J. Radiol. Open"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s41551-017-0116-7","article-title":"Iron oxide nanoclusters for T1 magnetic resonance imaging of non-human primates","volume":"1","author":"Lu","year":"2017","journal-title":"Nat. Biomed. Eng."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Poggiarelli, L., Bernetti, C., Pugliese, L., Greco, F., Beomonte Zobel, B., and Mallio, C.A. (2025). Manganese-Based Contrast Agents as Alternatives to Gadolinium: A Comprehensive Review. Clin. Pract., 15.","DOI":"10.3390\/clinpract15080137"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e230793","DOI":"10.1148\/radiol.230793","article-title":"Brain Tumor Imaging without Gadolinium-based Contrast Agents: Feasible or Fantasy?","volume":"310","author":"Wamelink","year":"2024","journal-title":"Radiology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9272","DOI":"10.1039\/D0NR01552K","article-title":"Continuous growth phenomenon for direct synthesis of monodisperse water-soluble iron oxide nanoparticles with extraordinarily high relaxivity","volume":"12","author":"Cheah","year":"2020","journal-title":"Nanoscale"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11520","DOI":"10.1038\/s41598-023-38222-6","article-title":"Iron oxide nanoparticles as positive T1 contrast agents for low-field magnetic resonance imaging at 64 mT","volume":"13","author":"Oberdick","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20523","DOI":"10.1021\/acsanm.3c04269","article-title":"Radiolabeled Iron Oxide Nanomaterials for Multimodal Nuclear Imaging and Positive Contrast Magnetic Resonance Imaging (MRI): A Review","volume":"6","author":"Pellico","year":"2023","journal-title":"ACS Appl. Nano Mater."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"424","DOI":"10.7150\/ntno.86467","article-title":"Magnetic Resonance Imaging and Iron-oxide Nanoparticles in the era of Personalized Medicine","volume":"7","author":"Rahman","year":"2023","journal-title":"Nanotheranostics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/978-1-4939-6840-4_4","article-title":"Magnetic Characterization of Iron Oxide Nanoparticles for Biomedical Applications","volume":"1570","author":"Unni","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1021\/acs.langmuir.0c03314","article-title":"Versatile Surface Functionalization of Water-Dispersible Iron Oxide Nanoparticles with Precisely Controlled Sizes","volume":"37","author":"Cheah","year":"2021","journal-title":"Langmuir"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"131673","DOI":"10.1016\/j.matchemphys.2025.131673","article-title":"Relaxivity and cytotoxicity of iron oxide nanoparticles with different coatings for contrast agents in magnetic resonance imaging","volume":"348","author":"Vargas","year":"2026","journal-title":"Mater. Chem. Phys."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"100875","DOI":"10.1016\/j.jsamd.2025.100875","article-title":"Iron oxide nanoparticles enhancing magnetic resonance imaging: A review of the latest advancements","volume":"10","author":"Aboushoushah","year":"2025","journal-title":"J. Sci. Adv. Mater. Devices"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"106054","DOI":"10.1016\/j.ebiom.2025.106054","article-title":"Superparamagnetic iron oxide nanoparticles in clinical applications: Current status and future perspectives","volume":"122","author":"Guo","year":"2025","journal-title":"EBioMedicine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1073\/pnas.1620145114","article-title":"Exceedingly small iron oxide nanoparticles as positive MRI contrast agents","volume":"114","author":"Wei","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/ird3.70035","article-title":"Ultrasmall Superparamagnetic Iron Oxide Nanoparticles as Positive Contrast Agents in Low-Field Magnetic Resonance Imaging","volume":"3","author":"Alford","year":"2025","journal-title":"Iradiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"168481","DOI":"10.1016\/j.jmmm.2021.168481","article-title":"The key role of reaction temperature on a polyol synthesis of water-dispersible iron oxide nanoparticles","volume":"540","author":"Cheah","year":"2021","journal-title":"J. Magn. Magn. Mater."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jmmm.2016.11.033","article-title":"A review of the magnetic properties, synthesis methods and applications of maghemite","volume":"426","author":"Shokrollahi","year":"2017","journal-title":"J. Magn. Magn. Mater."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1557\/s43578-023-01236-x","article-title":"The influence of the polyol solvents on the continuous growth of water-dispersible iron oxide nanoparticles","volume":"39","author":"Qu","year":"2024","journal-title":"J. Mater. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2284","DOI":"10.1021\/acsnano.7b00609","article-title":"Thermal Decomposition Synthesis of Iron Oxide Nanoparticles with Diminished Magnetic Dead Layer by Controlled Addition of Oxygen","volume":"11","author":"Unni","year":"2017","journal-title":"ACS Nano"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2147\/NSA.S99986","article-title":"Synthesis, characterization, applications, and challenges of iron oxide nanoparticles","volume":"9","author":"Ali","year":"2016","journal-title":"Nanotechnol. Sci. Appl."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.mseb.2012.01.003","article-title":"Synthesis and characterization of magnetite nanoparticles via the chemical co-precipitation method","volume":"177","author":"Petcharoen","year":"2012","journal-title":"Mater. Sci. Eng. B"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"56701","DOI":"10.1021\/acsami.0c13825","article-title":"In Situ One-Pot Synthesis of Fe2O3@BSA Core-Shell Nanoparticles as Enhanced T1-Weighted Magnetic Resonance Imagine Contrast Agents","volume":"12","author":"Xu","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Tao, C., Zheng, Q., An, L., He, M., Lin, J., Tian, Q., and Yang, S. (2019). T1-Weight Magnetic Resonance Imaging Performances of Iron Oxide Nanoparticles Modified with a Natural Protein Macromolecule and an Artificial Macromolecule. Nanomaterials, 9.","DOI":"10.3390\/nano9020170"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Baki, A., Remmo, A., L\u00f6wa, N., Wiekhorst, F., and Bleul, R. (2021). Albumin-Coated Single-Core Iron Oxide Nanoparticles for Enhanced Molecular Magnetic Imaging (MRI\/MPI). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126235"},{"key":"ref_34","first-page":"166","article-title":"Effect of coating thickness of iron oxide nanoparticles on their relaxivity in the MRI","volume":"19","author":"Hajesmaeelzadeh","year":"2016","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1002\/jmri.21194","article-title":"Coating thickness of magnetic iron oxide nanoparticles affects R2 relaxivity","volume":"26","author":"LaConte","year":"2007","journal-title":"J. Magn. Reson. Imaging JMRI"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7347","DOI":"10.1021\/acs.chemmater.5c01654","article-title":"Tuning the Surface States of Fe3O4 Nanoparticles for Enhanced Magnetic Anisotropy and Induction Efficacy","volume":"37","author":"Portwin","year":"2025","journal-title":"Chem. Mater."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1021\/acsanm.1c00311","article-title":"Engineering Shape Anisotropy of Fe3O4-\u03b3-Fe2O3 Hollow Nanoparticles for Magnetic Hyperthermia","volume":"4","author":"Niraula","year":"2021","journal-title":"ACS Appl. Nano Mater."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.1021\/acsnano.9b08570","article-title":"Quasi-amorphous and Hierarchical Fe2O3 Supraparticles: Active T1-Weighted Magnetic Resonance Imaging in Vivo and Renal Clearance","volume":"14","author":"Ma","year":"2020","journal-title":"ACS Nano"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1016\/j.apsusc.2007.09.063","article-title":"Analysis of XPS spectra of Fe2+ and Fe3+ ions in oxide materials","volume":"254","author":"Yamashita","year":"2008","journal-title":"Appl. Surf. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.bioorg.2017.12.033","article-title":"Bovine Serum Albumin (BSA) coated iron oxide magnetic nanoparticles as biocompatible carriers for curcumin-anticancer drug","volume":"76","author":"Nosrati","year":"2018","journal-title":"Bioorganic Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.colsurfb.2009.10.005","article-title":"Studies on interaction of colloidal Ag nanoparticles with Bovine Serum Albumin (BSA)","volume":"76","author":"Ravindran","year":"2010","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.pdpdt.2017.12.004","article-title":"Synthesis and characterization of small-sized gold nanoparticles coated by bovine serum albumin (BSA) for cancer photothermal therapy","volume":"21","author":"Taha","year":"2018","journal-title":"Photodiagnosis Photodyn. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cmmi.265","article-title":"Classification and basic properties of contrast agents for magnetic resonance imaging","volume":"4","author":"Geraldes","year":"2009","journal-title":"Contrast Media Mol. Imaging"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ahmadpoor, F., Masood, A., Feliu, N., Parak, W.J., and Shojaosadati, S.A. (2021). The effect of surface coating of iron oxide nanoparticles on magnetic resonance imaging relaxivity. Front. Nanotechnol., 3.","DOI":"10.3389\/fnano.2021.644734"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1021\/nn3046055","article-title":"Bisphosphonate-Anchored PEGylation and Radiolabeling of Superparamagnetic Iron Oxide: Long-Circulating Nanoparticles for in Vivo Multimodal (T1 MRI-SPECT) Imaging","volume":"7","author":"Sandiford","year":"2013","journal-title":"ACS Nano"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/3\/478\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T06:00:56Z","timestamp":1774418456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/3\/478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,23]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["biom16030478"],"URL":"https:\/\/doi.org\/10.3390\/biom16030478","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,23]]}}}