{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T21:44:17Z","timestamp":1789681457367,"version":"4.0.1"},"reference-count":37,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T00:00:00Z","timestamp":1700524800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32271374"],"award-info":[{"award-number":["32271374"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Small"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Magnetic resonance imaging contrast agents are frequently used in clinics to enhance the contrast between diseased and normal tissues. The previously reported poly(acrylic acid) stabilized exceedingly small gadolinium oxide nanoparticles (ES\u2010GdON\u2010PAA) overcame the problems of commercial Gd chelates, but limitations still exist, i.e., high <jats:italic>r<\/jats:italic><jats:sub>2<\/jats:sub>\/<jats:italic>r<\/jats:italic><jats:sub>1<\/jats:sub> ratio, long blood circulation half\u2010life, and no data for large scale synthesis and formulation optimization. In this study, polymaleic acid (PMA) is found to be an ideal stabilizer to synthesize ES\u2010GdONs. Compared with ES\u2010GdON\u2010PAA, the PMA\u2010stabilized ES\u2010GdON (ES\u2010GdON\u2010PMA) has a lower <jats:italic>r<\/jats:italic><jats:sub>2<\/jats:sub>\/<jats:italic>r<\/jats:italic><jats:sub>1<\/jats:sub> ratio (2.05, 7.0 T) and a lower blood circulation half\u2010life (37.51\u00a0min). The optimized ES\u2010GdON\u2010PMA\u20109 has an exceedingly small particle size (2.1\u00a0nm), excellent water dispersibility, and stability. A facile, efficient, and environmental friendly synthetic method is developed for large\u2010scale synthesis of the ES\u2010GdONs\u2010PMA. The weight of the optimized freeze\u2013dried ES\u2010GdON\u2010PMA\u201026 synthesized in a 20\u00a0L of reactor reaches the kilogram level. The formulation optimization is also finished, and the concentrated ES\u2010GdON\u2010PMA\u201026 formulation (<jats:italic>C<\/jats:italic><jats:sub>Gd<\/jats:sub>\u00a0=\u00a0100\u00a0m<jats:sc>m<\/jats:sc>) after high\u2010pressure steam sterilization possesses eligible physicochemical properties (i.e., pH value, osmolality, viscosity, and density) for investigational new drug application.<\/jats:p>","DOI":"10.1002\/smll.202308547","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T19:58:49Z","timestamp":1700683129000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Kilogram\u2010Scale Synthesis of Extremely Small Gadolinium Oxide Nanoparticles as a <i>T<\/i><sub>1<\/sub>\u2010Weighted Contrast Agent for Magnetic Resonance Imaging"],"prefix":"10.1002","volume":"20","author":[{"given":"Lihe","family":"Wu","sequence":"first","affiliation":[{"name":"School of Biomedical 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