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that enables tumor-selective heating (+2.5 \u00b0C). In this study, we investigated whether mEHT accelerates the tumor-specific delivery of doxorubicin (DOX) from lyso-thermosensitive liposomal doxorubicin (LTLD) and improves its anticancer efficacy in mice bearing a triple-negative breast cancer cell line (4T1). The 4T1 cells were orthotopically injected into Balb\/C mice, and mEHT was performed on days 9, 12, and 15 after the implantation. DOX, LTLD, or PEGylated liposomal DOX (PLD) were administered for comparison. The tumor size and DOX accumulation in the tumor were measured. The cleaved caspase-3 (cC3) and cell proliferation were evaluated by cC3 or Ki67 immunohistochemistry and Western blot. The LTLD+mEHT combination was more effective at inhibiting tumor growth than the free DOX and PLD, demonstrated by reductions in both the tumor volume and tumor weight. LTLD+mEHT resulted in the highest DOX accumulation in the tumor one hour after treatment. Tumor cell damage was associated with cC3 in the damaged area, and with a reduction in Ki67 in the living area. These changes were significantly the strongest in the LTLD+mEHT-treated tumors. The body weight loss was similar in all mice treated with any DOX formulation, suggesting no difference in toxicity. In conclusion, LTLD combined with mEHT represents a novel approach for DOX delivery into cancer tissue.<\/jats:p>","DOI":"10.3390\/ijms25063101","type":"journal-article","created":{"date-parts":[[2024,3,7]],"date-time":"2024-03-07T08:59:37Z","timestamp":1709801977000},"page":"3101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Modulated Electro-Hyperthermia Accelerates Tumor Delivery and Improves Anticancer Activity of Doxorubicin Encapsulated in Lyso-Thermosensitive Liposomes in 4T1-Tumor-Bearing Mice"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4806-7477","authenticated-orcid":false,"given":"Kenan","family":"Aloss","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6812-374X","authenticated-orcid":false,"given":"Syeda Mahak Zahra","family":"Bokhari","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5371-5322","authenticated-orcid":false,"given":"Pedro Henrique","family":"Leroy Viana","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nino","family":"Giunashvili","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csaba Andr\u00e1s","family":"Schvarcz","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"},{"name":"HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"Sz\u00e9n\u00e1si","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"B\u00f3csi","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Ko\u00f3s","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4296-2761","authenticated-orcid":false,"given":"Gert","family":"Storm","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 Utrecht, The Netherlands"},{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8577-4475","authenticated-orcid":false,"given":"Zsuzsanna","family":"Mikl\u00f3s","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"},{"name":"National Kor\u00e1nyi Institute for Pulmonology, 1122 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Beny\u00f3","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"},{"name":"HUN-REN-SU Cerebrovascular and Neurocognitive Diseases Research Group, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1095-3564","authenticated-orcid":false,"given":"P\u00e9ter","family":"Hamar","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e000357","DOI":"10.1136\/esmoopen-2018-000357","article-title":"How shall we treat early triple-negative breast cancer (TNBC): From the current standard to upcoming immuno-molecular strategies","volume":"3","author":"Park","year":"2018","journal-title":"ESMO Open"},{"key":"ref_2","first-page":"567","article-title":"Anthracycline-induced cardiotoxicity and the cardiac-sparing effect of liposomal formulation","volume":"2","author":"Rahman","year":"2007","journal-title":"Int. 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