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Several promising approaches have been developed to increase MRI sensitivity, one of which is Overhauser dynamic nuclear polarization (ODNP)-enhanced MRI (OMRI). In this study, a macromolecular construct based on human serum albumin and nitroxyl radicals (HSA-NIT) was developed using a new synthesis method that significantly increased the modification to 21 nitroxide residues per protein. This was confirmed by electron paramagnetic resonance (EPR) spectroscopy and matrix-assisted laser desorption\/ionization time-of-flight (MALDI ToF) mass spectrometry. Gel electrophoresis and circular dichroism showed no significant changes in the structure of HSA-NITs, and no oligomers were formed during modification. The cytotoxicity of HSA-NITs was comparable to that of native albumin. HSA-NITs were evaluated as potential \u201cmetal-free\u201d organic radical relaxation-based contrast agents for 1H-MRI and as hyperpolarizing contrast agents for OMRI. Relaxivities (longitudinal and transversal relaxation rates r1 and r2) for HSA-NITs were measured at different magnetic field strengths (1.88, 3, 7, and 14 T). Phantoms were used to demonstrate the potential use of HSA-NIT as a T1- and T2-weighted relaxation-based contrast agent at 3 T and 14 T. The efficacy of 1H Overhauser dynamic nuclear polarization (ODNP) in liquids at an ultralow magnetic field (ULF, B0 = 92 \u00b1 0.8 \u03bcT) was investigated for HSA-NIT conjugates. The HSA-NITs themselves did not show ODNP enhancement; however, under the proteolysis conditions simulating cancer tissue, HSA-NIT conjugates were cleaved into lower-molecular-weight (MW) protein fragments that activate ODNP capabilities, resulting in a maximum achievable enhancement |Emax| of 40\u201350 and a radiofrequency power required to achieve half of Emax, P1\/2, of 21\u201327 W. The HSA-NIT with a higher degree of modification released increased the number of spin probes upon biodegradation, which significantly enhanced the Overhauser effect. Thus, HSA-NITs may represent a new class of MRI relaxation-based contrast agents as well as novel cleavable conjugates for use as hyperpolarizing contrast agents (HCAs) in OMRI.<\/jats:p>","DOI":"10.3390\/ijms25074041","type":"journal-article","created":{"date-parts":[[2024,4,5]],"date-time":"2024-04-05T02:25:32Z","timestamp":1712283932000},"page":"4041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Contrast Agents Based on Human Serum Albumin and Nitroxides for 1H-MRI and Overhauser-Enhanced MRI"],"prefix":"10.3390","volume":"25","author":[{"given":"Dmitry","family":"Mitin","sequence":"first","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine SB RAS, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedemann","family":"Bullinger","sequence":"additional","affiliation":[{"name":"High-Field Magnetic Resonance Center, Max Planck Institute for Biological Cybernetics, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3486-0335","authenticated-orcid":false,"given":"Sergey","family":"Dobrynin","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn","family":"Engelmann","sequence":"additional","affiliation":[{"name":"High-Field Magnetic Resonance Center, Max Planck Institute for Biological Cybernetics, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Scheffler","sequence":"additional","affiliation":[{"name":"High-Field Magnetic Resonance Center, Max Planck Institute for Biological Cybernetics, 72076 Tuebingen, Germany"},{"name":"Department of Biomedical Magnetic Resonance, Eberhard-Karls University, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8817-7358","authenticated-orcid":false,"given":"Mikhail","family":"Kolokolov","sequence":"additional","affiliation":[{"name":"International Tomography Center SB RAS, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0777-5103","authenticated-orcid":false,"given":"Olesya","family":"Krumkacheva","sequence":"additional","affiliation":[{"name":"International Tomography Center SB RAS, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Buckenmaier","sequence":"additional","affiliation":[{"name":"High-Field Magnetic Resonance Center, Max Planck Institute for Biological Cybernetics, 72076 Tuebingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6033-0368","authenticated-orcid":false,"given":"Igor","family":"Kirilyuk","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5708-7595","authenticated-orcid":false,"given":"Alexey","family":"Chubarov","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology and Fundamental Medicine SB RAS, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yousaf, T., Dervenoulas, G., and Politis, M. (2018). Advances in MRI Methodology, Elsevier Inc.. [1st ed.].","DOI":"10.1016\/bs.irn.2018.08.008"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"639","DOI":"10.4155\/fmc-2017-0215","article-title":"Gadolinium as an MRI contrast agent","volume":"10","author":"Kim","year":"2018","journal-title":"Future Med. 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