{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T14:26:37Z","timestamp":1786803997750,"version":"build-2736575974"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"22","license":[{"start":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T00:00:00Z","timestamp":1540944000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T00:00:00Z","timestamp":1540944000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T00:00:00Z","timestamp":1540944000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81473120"],"award-info":[{"award-number":["81473120"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hospital Pharmaceutical Research Foundation of Changzhou Siyao Pharmaceuticals Co., Ltd.","award":["2014YX011"],"award-info":[{"award-number":["2014YX011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,11,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL1, GdL2, and GdL3, by conjugating rhein with gadolinium 2-[4,7,10-tris\u00ad(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]\u00adacetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM\u20131 s\u20131) were found to be higher than that of Gd-DOTA (4.28 mM\u20131 s\u20131). Necrosis avidity of GdL1 was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5\u201312 h. Besides, L1 was also labeled with 64Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a \u03b3-counter. The uptakes of 64CuL1 in necrotic liver and muscle were higher than those in normal liver and muscle (P &amp;lt; 0.05). Then, the ability of GdL1 to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 \u00b1 0.11 at 3 h after administration of GdL1. Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL1 may serve as a promising MRI contrast agent for accurate assessment of treatment response.<\/jats:p>","DOI":"10.1021\/acs.analchem.8b01868","type":"journal-article","created":{"date-parts":[[2018,10,31]],"date-time":"2018-10-31T11:53:57Z","timestamp":1540986837000},"page":"13249-13256","source":"Crossref","is-referenced-by-count":15,"title":["Synthesis and Biological Evaluation of Rhein-Based\nMRI Contrast Agents for in Vivo Visualization of Necrosis"],"prefix":"10.1021","volume":"90","author":[{"given":"Li","family":"Bian","sequence":"first","affiliation":[{"name":"Nanjing University of Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Gao","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4821-6620","authenticated-orcid":true,"given":"Dongjian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiyan","family":"Ji","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"China Pharmaceutical University , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Su","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"China Pharmaceutical University , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghua","family":"Duan","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"China Pharmaceutical University , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Luo","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"China Pharmaceutical University , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejian","family":"Huang","sequence":"additional","affiliation":[{"name":"Nanjing University of Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanbo","family":"Feng","sequence":"additional","affiliation":[{"name":"Nanjing University of Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yicheng","family":"Ni","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]},{"name":"KU Leuven , , ,","place":["Leuven, Belgium, 3000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqi","family":"Yin","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8559-9125","authenticated-orcid":true,"given":"Qiaomei","family":"Jin","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8402-9753","authenticated-orcid":true,"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Province Academy of Traditional Chinese Medicine , , , ,","place":["Nanjing, Jiangsu Province, P. R. China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2018,10,31]]},"reference":[{"key":"2026081502114218700_cit1","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1200\/JCO.2006.08.2305","article-title":"Use of Positron Emission Tomography\nfor Response Assessment of Lymphoma: Consensus of the Imaging Subcommittee\nof International Harmonization Project in Lymphoma","volume":"25","author":"Juweid","year":"2007","journal-title":"J. Clin. 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Med."},{"key":"2026081502114218700_cit3","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1002\/1097-0142(19810101)47:1&lt;207::AID-CNCR2820470134&gt;3.0.CO;2-6","article-title":"Reporting\nResults of\nCancer Treatment","volume":"47","author":"Miller","year":"1981","journal-title":"Cancer"},{"key":"2026081502114218700_cit4","first-page":"2495","article-title":"New Response Evaluation\nCriteria in Solid Tumours: Revised RECIST\nGuideline (Version 1.1)","volume":"36","author":"Watanabe","year":"2009","journal-title":"Gan to Kagaku Ryoho."},{"key":"2026081502114218700_cit5","doi-asserted-by":"publisher","first-page":"239","DOI":"10.6004\/jnccn.2015.0030","article-title":"Value of Functional\nImaging by PET in Esophageal Cancer","volume":"13","author":"Schmidt","year":"2015","journal-title":"J. Natl.\nCompr. Cancer Network"},{"issue":"Suppl 1","key":"2026081502114218700_cit6","doi-asserted-by":"publisher","first-page":"34S","DOI":"10.2967\/jnumed.115.157875","article-title":"18F-FDG PET\/CT for Monitoring\nof Treatment Response in Breast Cancer","volume":"57","author":"Avril","year":"2016","journal-title":"J. Nucl.\nMed."},{"key":"2026081502114218700_cit7","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/s13139-016-0449-2","article-title":"Comparison of Quantitative Methods\non FDG PET\/CT for Treatment Response Evaluation of Metastatic Colorectal\nCancer","volume":"51","author":"Bang","year":"2017","journal-title":"Nucl. Med. Mol. Imaging"},{"key":"2026081502114218700_cit8","doi-asserted-by":"publisher","first-page":"342","DOI":"10.4048\/jbc.2013.16.3.342","article-title":"Early Prediction of\nTumor Response:\nA Future Strategy for Optimizing Cancer Treatment","volume":"16","author":"Ueda","year":"2013","journal-title":"J. Breast Cancer."},{"key":"2026081502114218700_cit9","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1007\/s00330-005-0088-y","article-title":"False-Positive\nFDG\nPET Pptake--The Role of PET\/CT","volume":"16","author":"Rosenbaum","year":"2006","journal-title":"Eur. Radiol."},{"key":"2026081502114218700_cit10","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1158\/1078-0432.CCR-0642-03","article-title":"Vascular\nTargeting Agents as Cancer Therapeutics","volume":"10","author":"Thorpe","year":"2004","journal-title":"Clin.\nCancer Res."},{"key":"2026081502114218700_cit11","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1007\/s00330-005-0094-0","article-title":"Magnetic Resonance\nImaging After Radiofrequency Ablation in A Rodent Model of Liver Tumor:\nTissue Characterization Using A Novel Necrosis-Avid Contrast Agent","volume":"16","author":"Ni","year":"2006","journal-title":"Eur. Radiol."},{"key":"2026081502114218700_cit12","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.1021\/bc3003309","article-title":"Biomarkers and Molecular Probes for\nCell Death Imaging\nand Targeted Therapeutics","volume":"23","author":"Smith","year":"2012","journal-title":"Bioconjugate Chem."},{"key":"2026081502114218700_cit13","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.ejmech.2013.11.029","article-title":"Recent Advances in Small Organic\nMolecules as DNA Intercalating\nAgents: Synthesis, Activity, and Modeling","volume":"74","author":"Rescifina","year":"2014","journal-title":"Eur.\nJ. Med. Chem."},{"key":"2026081502114218700_cit14","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1002\/med.21391","article-title":"Anthraquinones as Pharmacological Tools and Drugs","volume":"36","author":"Malik","year":"2016","journal-title":"Med. Res. Rev."},{"key":"2026081502114218700_cit15","doi-asserted-by":"publisher","first-page":"21341","DOI":"10.1038\/srep21341","article-title":"Discovery of Radioiodinated Monomeric Anthraquinones as a Novel Class\nof Necrosis Avid Agents for Early Imaging of Necrotic Myocardium","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"2026081502114218700_cit16","doi-asserted-by":"publisher","first-page":"1260","DOI":"10.1021\/acs.analchem.6b03959","article-title":"Radiolabeled\nRhein as Small-Molecule Necrosis Avid Agents for Imaging of Necrotic\nMyocardium","volume":"89","author":"Luo","year":"2017","journal-title":"Anal. Chem."},{"key":"2026081502114218700_cit17","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1021\/acsmedchemlett.6b00398","article-title":"Novel 18F-Labeled 1-Hydroxyanthraquinone Derivatives for Necrotic Myocardium\nImaging","volume":"8","author":"Ji","year":"2017","journal-title":"ACS Med. Chem. Lett."},{"key":"2026081502114218700_cit18","doi-asserted-by":"publisher","first-page":"2694","DOI":"10.1002\/adma.201304744","article-title":"Anchoring Group\nEffects of Surface Ligands on Magnetic\nProperties of Fe3O4 Nanoparticles: Towards High\nPerformance MRI Contrast Agents","volume":"26","author":"Zeng","year":"2014","journal-title":"Adv. Mater."},{"key":"2026081502114218700_cit19","doi-asserted-by":"publisher","first-page":"1701095","DOI":"10.1002\/adma.201701095","article-title":"Tumor Microenvironment-Triggered\nAggregation of Antiphagocytosis 99mTc-Labeled Fe3O4 Nanoprobes for Enhanced\nTumor Imaging In Vivo","volume":"29","author":"Gao","year":"2017","journal-title":"Adv. Mater."},{"key":"2026081502114218700_cit20","doi-asserted-by":"publisher","first-page":"1702700","DOI":"10.1002\/smll.201702700","article-title":"Biodegradable\nNanoagents with Short\nBiological Half-Life for SPECT\/PAI\/MRI Multimodality Imaging and PTT\nTherapy of Tumors","volume":"14","author":"Chen","year":"2018","journal-title":"Small"},{"key":"2026081502114218700_cit21","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1007\/s00259-007-0689-6","article-title":"Could 99mTc-glucarate\nBe Used to Evaluate Tumour Necrosis?","volume":"35","author":"Perek","year":"2008","journal-title":"Eur. J.\nNucl. Med. Mol. Imaging"},{"key":"2026081502114218700_cit22","doi-asserted-by":"publisher","first-page":"180","DOI":"10.3109\/1061186X.2014.971328","article-title":"Experimental\nEvaluation of Radioiodinated\nSennoside B as A Necrosis-Avid Tracer Agent","volume":"23","author":"Zhang","year":"2015","journal-title":"J. Drug Target."},{"key":"2026081502114218700_cit23","first-page":"291","article-title":"A Review on Anthaquinones Isolated\nfrom Cassia Species\nand Their Applications","volume":"3","author":"Dave","year":"2012","journal-title":"Indian J. Nat. Prod\nResour."},{"key":"2026081502114218700_cit24","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1021\/cr00081a003","article-title":"Paramagnetic\nMetal Complexes as Water Proton Relaxation Agents for NMR Imaging:\nTheory and Design","volume":"87","author":"Lauffer","year":"1987","journal-title":"Chem. Rev."},{"key":"2026081502114218700_cit25","doi-asserted-by":"publisher","first-page":"9333","DOI":"10.1021\/ja961743g","article-title":"Structural and Dynamic Parameters\nObtained from 17O NMR, EPR, and NMRD Studies of Monomeric\nand Dimeric Gd3+ Complexes of Interest in Magnetic Resonance\nImaging: An Integrated and Theoretically Self-Consistent Approach","volume":"118","author":"Powell","year":"1996","journal-title":"J. Am. Chem. Soc."},{"key":"2026081502114218700_cit26","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1021\/jm100966t","article-title":"Gd-Complexes of 1,4,7,10-Tetraazacyclododecane-N,N\u2032,N\u2033,N\u2034-1,4,7,10-tetraacetic Acid\n(DOTA) Conjugates of Tranexamates as a New Class of Blood-Pool Magnetic\nResonance Imaging Contrast Agents","volume":"54","author":"Gu","year":"2011","journal-title":"J. Med. Chem."},{"key":"2026081502114218700_cit27","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1097\/01.rli.0000112789.57341.01","article-title":"Comparison\nof Gd\u00ad(DTPA-BMA) (Omniscan)\nVersus Gd\u00ad(HP-DO3A) (ProHance) Retention in Human Bone Tissue by Inductively\nCoupled Plasma Atomic Emission Spectroscopy","volume":"39","author":"Gibby","year":"2004","journal-title":"Invest. Radiol."},{"key":"2026081502114218700_cit28","first-page":"65","article-title":"Magnetic\nResonance Contrast Media: Principles and Progress","volume":"6","author":"Lauffer","year":"1990","journal-title":"Magn Reson Q."},{"key":"2026081502114218700_cit29","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1007\/s00259-007-0624-x","article-title":"99mTc Hynic-Rh-Annexin V Scintigraphy for\nin Vivo Imaging of Apoptosis in Patients with Head and Neck Cancer\nTreated with Chemoradiotherapy","volume":"35","author":"Hoebers","year":"2008","journal-title":"Eur. J. Nucl.\nMed. Mol. Imaging"},{"key":"2026081502114218700_cit30","first-page":"2766","article-title":"Increased\nUptake of\nThe Apoptosis-Imaging Agent (99m)Tc Recombinant Human Annexin V in\nHuman Tumors after One Course of Chemotherapy as A Predictor of Tumor\nResponse and Patient Prognosis","volume":"8","author":"Belhocine","year":"2002","journal-title":"Clin. Cancer\nRes."},{"key":"2026081502114218700_cit31","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1016\/j.bbamcr.2008.01.030","article-title":"Extracellular Annexin A5: Functions of Phosphatidylserine-Binding\nand Two-Dimensional Crystallization","volume":"1783","author":"van\nGenderen","year":"2008","journal-title":"Biochim.\nBiophys. Acta, Mol. Cell Res."},{"key":"2026081502114218700_cit32","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1016\/S0360-3016(02)03928-7","article-title":"Phosphatidylserine Is A Marker of Tumor Vasculature\nand A Potential Target for Cancer Imaging and Therapy","volume":"54","author":"Ran","year":"2002","journal-title":"Int. J. Radiat. Oncol., Biol., Phys."},{"key":"2026081502114218700_cit33","doi-asserted-by":"publisher","first-page":"3300","DOI":"10.1021\/ol100923d","article-title":"Hoechst-IR:\nAn Imaging Agent That\nDetects Necrotic Tissue in Vivo by Binding Extracellular DNA","volume":"12","author":"Dasari","year":"2010","journal-title":"Org. Lett."},{"key":"2026081502114218700_cit34","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1080\/02841850801958890","article-title":"Increased\nExpression of Vascular Endothelial Growth Factor in Hepatocellular\nCarcinoma after Transcatheter Arterial Chemoembolization","volume":"49","author":"Wang","year":"2008","journal-title":"Acta Radiol."},{"key":"2026081502114218700_cit35","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1148\/radiol.11110144","article-title":"Local-Regional Treatment\nof Hepatocellular Carcinoma","volume":"262","author":"Lencioni","year":"2012","journal-title":"Radiology"},{"key":"2026081502114218700_cit36","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1007\/s00270-009-9697-1","article-title":"The March of Extrahepatic\nCollaterals: Analysis of Blood Supply to Hepatocellular Carcinoma\nLocated in The Bare Area of The Liver after Chemoembolization","volume":"33","author":"Miyayama","year":"2010","journal-title":"Cardiovasc Intervent Radiol."},{"key":"2026081502114218700_cit37","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1039\/c0ib00135j","article-title":"A Perspective\non Vascular Disrupting Agents That Interact with Tubulin: Preclinical\nTumor Imaging and Biological Assessment","volume":"3","author":"Mason","year":"2011","journal-title":"Integr\nBiol. (Camb)."},{"key":"2026081502114218700_cit38","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1517\/13543780802691068","article-title":"A Review and Update of The Current\nStatus of The Vasculature-Disabling Agent Combretastatin-A4 Phosphate\n(CA4P)","volume":"18","author":"Siemann","year":"2009","journal-title":"Expert Opin. Invest. Drugs"}],"container-title":["Analytical Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.analchem.8b01868","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/90\/22\/13249\/8493791\/ac8b01868.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/ancham\/article-pdf\/90\/22\/13249\/8493791\/ac8b01868.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T13:30:10Z","timestamp":1786800610000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/ancham\/article\/90\/22\/13249\/820373\/Synthesis-and-Biological-Evaluation-of-Rhein-Based"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,31]]},"references-count":38,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2018,10,31]]},"published-print":{"date-parts":[[2018,11,20]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.analchem.8b01868","relation":{},"ISSN":["0003-2700","1520-6882"],"issn-type":[{"value":"0003-2700","type":"print"},{"value":"1520-6882","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,31]]}}}