{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T00:49:59Z","timestamp":1768351799341,"version":"3.49.0"},"reference-count":33,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T00:00:00Z","timestamp":1607644800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning","award":["2017R1A2B4004951"],"award-info":[{"award-number":["2017R1A2B4004951"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Purpose<\/jats:title>\n<jats:p>To assess the feasibility of the combined sorafenib (SOR) and doxorubicin-loaded microbubble-albumin nanoparticle complex (DOX-MAC) treatment effect in an orthotopic rat model of hepatocellular carcinoma (HCC).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>Sixty-two rats with N1-S1 hepatoma were divided into four groups according to the treatment methods, i.e. G1 (SOR and DOX-MAC; n = 12), G2 (SOR; n = 15), G3 (DOX-MAC; n = 12), G4 (DOX; n = 11), and G5 (normal saline; n = 12). We performed the theragnostic, contrast-enhanced ultrasound examination and treatment at the baseline, one-week, and two-weeks. Tumor volume and perfusion parameters were compared at each time point and the differences between all of the groups over time were analyzed using repeated measures ANOVA. We also analyzed the apoptotic index and microvessel density (MVD) per each tumor specimen in all of the groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The tumors increased from the beginning in all of the groups to the final follow-up, whereas the tumor growth in the G1 group and the G2 group was inhibited during the treatment period compared to the baseline tumor volume (<jats:italic>P<\/jats:italic> = 0.016 and <jats:italic>P<\/jats:italic> = 0.031). The G1 group resulted in tumor growth inhibition compared to the control group (<jats:italic>P<\/jats:italic> = 0.008). The G1 group showed that the peak enhancement and wash-in area under the curve were lower than that of the G4 group (<jats:italic>P<\/jats:italic> = 0.010 and 0.022). However, there was no difference in perfusion parameters in the other treated group compared to control group. The MVD of the G1 group tumor was lower than that of the G4 group (<jats:italic>P<\/jats:italic> = .016).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our results suggest that the combination therapy of SOR and DOX-MAC can cause inhibition of tumor growth after treatment and that this therapy can be adequately monitored using the theragnostic DOX-MAC agent.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0243815","type":"journal-article","created":{"date-parts":[[2020,12,11]],"date-time":"2020-12-11T18:59:16Z","timestamp":1607713156000},"page":"e0243815","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Combined treatment of sorafenib and doxorubicin-loaded microbubble-albumin nanoparticle complex for hepatocellular carcinoma: A feasibility study"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1858-0640","authenticated-orcid":true,"given":"Seunghyun","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8090-7758","authenticated-orcid":true,"given":"Jung Hoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyungwon","family":"Moon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hak Jong","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joon 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Zhai","year":"2013","journal-title":"World J Hepatol"},{"issue":"2","key":"pone.0243815.ref021","doi-asserted-by":"crossref","first-page":"179","DOI":"10.7863\/ultra.34.2.179","article-title":"Dynamic contrast-enhanced ultrasound for quantification of tissue perfusion","volume":"34","author":"E Frohlich","year":"2015","journal-title":"J Ultrasound Med"},{"issue":"4","key":"pone.0243815.ref022","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1158\/1078-0432.CCR-09-2175","article-title":"Metastatic renal cell carcinoma treated with sunitinib: early evaluation of treatment response using dynamic contrast-enhanced ultrasonography","volume":"16","author":"N Lassau","year":"2010","journal-title":"Clin Cancer Res"},{"issue":"4","key":"pone.0243815.ref023","doi-asserted-by":"crossref","first-page":"577","DOI":"10.7863\/jum.2010.29.4.577","article-title":"Determination of Breast Cancer Response to Bevacizumab Therapy Using Contrast-Enhanced Ultrasound and Artificial Neural 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