{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T03:19:12Z","timestamp":1785467952301,"version":"3.56.0"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["STARTING 149496"],"award-info":[{"award-number":["STARTING 149496"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["PD146216"],"award-info":[{"award-number":["PD146216"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["PD 142272"],"award-info":[{"award-number":["PD 142272"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["K147410"],"award-info":[{"award-number":["K147410"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["K142385"],"award-info":[{"award-number":["K142385"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["RRF-2.3.1-21-2022-00015"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00015"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["ADVANCED\/150077"],"award-info":[{"award-number":["ADVANCED\/150077"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018818","name":"National Research, Development and Innovation Office","doi-asserted-by":"publisher","award":["RRF-2.3.1-21-2022-00015"],"award-info":[{"award-number":["RRF-2.3.1-21-2022-00015"]}],"id":[{"id":"10.13039\/501100018818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018694","name":"HORIZON EUROPE Marie Sklodowska-Curie Actions","doi-asserted-by":"publisher","award":["Grant agreement ID: 101065044"],"award-info":[{"award-number":["Grant agreement ID: 101065044"]}],"id":[{"id":"10.13039\/100018694","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["IPPTO 59.doc.funds"],"award-info":[{"award-number":["IPPTO 59.doc.funds"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["IPPTO 59.doc.funds"],"award-info":[{"award-number":["IPPTO 59.doc.funds"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Cancer"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chemotherapy remains the cornerstone of cancer treatment despite its well-documented challenges, including toxic side effects and drug resistance. Here, we demonstrate that a novel, highly toxic, daunosamine-modified derivative of daunorubicin (2-pyrrolino-daunorubicin, PyDau) can be safely administered to mice when encapsulated in liposome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>PyDau was synthesized from daunorubicin in a one-step reaction. Its increased in vitro cytotoxicity was confirmed across 42 human cell lines representing 12 cancer types, including multidrug resistant cells. The activity profile of this new derivative was analyzed in the context of 13 commonly used cancer drugs across a panel of lymphoblast cell lines missing individual components of DNA-repair enzymes. To enable in vivo application, PyDau was encapsulated in pegylated liposome, resulting in liposomal PyDau (LiPyDau). In vivo efficacy of LiPyDau was evaluated in three allograft models (melanoma, breast, lung), a xenograft model (uterine sarcoma), a patient-derived xenograft model (lung), and a genetically engineered mouse model of mammary cancer, including two models of drug resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>While PyDau exhibited up to 1000-fold greater cytotoxicity than daunomycin and doxorubicin against cancer cell lines, its in vivo application was hindered by an extremely narrow therapeutic window. Liposomal nanoformulation mitigated the limiting toxicity, allowing LiPyDau to be tested in preclinical allograft and xenograft mouse models. LiPyDau demonstrated robust efficacy across all models including multidrug-resistant cancer, completely eradicating tumors in a genetically engineered mouse model of triple-negative breast cancer. LiPyDau exerts its anticancer effect through a unique mechanism involving the crosslinking of complementary DNA strands, resulting in irreversible DNA damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Liposomal formulations of extremely cytotoxic anthracycline analogs, such as LiPyDau, represent a promising and highly effective therapeutic approach for combating drug resistant cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-025-02444-1","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T10:59:17Z","timestamp":1761562757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Safe delivery of a highly toxic anthracycline derivative through liposomal nanoformulation achieves complete cancer regression"],"prefix":"10.1186","volume":"24","author":[{"given":"Andr\u00e1s","family":"F\u00fcredi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szil\u00e1rd","family":"T\u00f3th","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krist\u00f3f","family":"Heged\u00fcs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e1l T.","family":"Szab\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anik\u00f3","family":"Ga\u00e1l","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerg\u0151","family":"Barta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00edvia N.","family":"Nasz\u00e1lyi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Kiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kata","family":"B\u00f6lcskei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Szeltner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Bajtai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal\u00e1zs","family":"Gombos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"Kiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mih\u00e1ly T.","family":"Cserepes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Kiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Pokreisz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Kenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"H\u00f6gler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Csaba","family":"Magyar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie D.","family":"Cowles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Csiszar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f3zsef","family":"T\u00f3v\u00e1ri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1vid","family":"Sz\u00fcts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsuzsanna","family":"Helyes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Varga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"Mez\u0151","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gergely","family":"Szak\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"2444_CR1","first-page":"409","volume":"72","author":"KD Miller","year":"2022","unstructured":"Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72:409\u201336.","journal-title":"CA Cancer J Clin"},{"key":"2444_CR2","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1002\/cmdc.202000131","volume":"15","author":"MB Martins-Teixeira","year":"2020","unstructured":"Martins-Teixeira MB, Carvalho I. Antitumour anthracyclines: progress and perspectives. ChemMedChem. 2020;15:933\u201348.","journal-title":"ChemMedChem"},{"key":"2444_CR3","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s10557-016-6711-0","volume":"31","author":"JV McGowan","year":"2017","unstructured":"McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc Drugs Ther. 2017;31:63\u201375.","journal-title":"Cardiovasc Drugs Ther"},{"key":"2444_CR4","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/s43018-019-0020-z","volume":"1","author":"CA Stewart","year":"2020","unstructured":"Stewart CA, Gay CM, Xi Y, Sivajothi S, Sivakamasundari V, Fujimoto J, et al. Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer. Nat Cancer. 2020;1:423\u201336.","journal-title":"Nat Cancer"},{"key":"2444_CR5","doi-asserted-by":"crossref","unstructured":"Fran\u00e7a GS, Baron M, King BR, Bossowski JP, Bjornberg A, Pour M et al. Cellular adaptation to cancer therapy along a resistance continuum. Nature. 2024;631:876\u201383.","DOI":"10.1038\/s41586-024-07690-9"},{"key":"2444_CR6","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nrd1984","volume":"5","author":"G Szak\u00e1cs","year":"2006","unstructured":"Szak\u00e1cs G, Paterson JK, Ludwig JA, Booth-Genthe C, Gottesman MM. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5:219\u201334.","journal-title":"Nat Rev Drug Discov"},{"key":"2444_CR7","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.1016\/S0140-6736(18)33137-4","volume":"393","author":"Increasing the dose","year":"2019","unstructured":"Increasing the dose. Intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37\u2008298 women with early breast cancer in 26 randomised trials. Lancet. 2019;393:1440\u201352.","journal-title":"Lancet"},{"key":"2444_CR8","doi-asserted-by":"publisher","first-page":"101205","DOI":"10.1016\/j.mam.2023.101205","volume":"93","author":"R Mattioli","year":"2023","unstructured":"Mattioli R, Ilari A, Colotti B, Mosca L, Fazi F, Colotti G. Doxorubicin and other anthracyclines in cancers: activity, chemoresistance and its overcoming. Mol Aspects Med. 2023;93:101205.","journal-title":"Mol Aspects Med"},{"key":"2444_CR9","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.jconrel.2012.03.020","volume":"160","author":"Y Barenholz","year":"2012","unstructured":"Barenholz Y. Doxil\u00ae--the first FDA-approved nano-drug: lessons learned. J Control Release. 2012;160:117\u201334.","journal-title":"J Control Release"},{"key":"2444_CR10","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.3390\/pharmaceutics14081725","volume":"14","author":"Z-H Peng","year":"2022","unstructured":"Peng Z-H, Jogdeo CM, Li J, Xie Y, Wang Y, Sheinin YM, et al. Tumor Microenvironment-Responsive polymeric iRGD and doxorubicin conjugates reduce spontaneous lung metastasis in an orthotopic breast cancer model. Pharmaceutics. 2022;14:1725.","journal-title":"Pharmaceutics"},{"key":"2444_CR11","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.2174\/1871520621666201229115612","volume":"21","author":"L Zhu","year":"2021","unstructured":"Zhu L, Lin M. The synthesis of Nano-Doxorubicin and its anticancer effect. Anticancer Agents Med Chem. 2021;21:2466\u201377.","journal-title":"Anticancer Agents Med Chem"},{"key":"2444_CR12","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1021\/jm050800q","volume":"49","author":"L Fang","year":"2006","unstructured":"Fang L, Zhang G, Li C, Zheng X, Zhu L, Xiao JJ, et al. Discovery of a Daunorubicin analogue that exhibits potent antitumor activity and overcomes P-gp-mediated drug resistance. J Med Chem. 2006;49:932\u201341.","journal-title":"J Med Chem"},{"key":"2444_CR13","doi-asserted-by":"publisher","first-page":"2464","DOI":"10.1073\/pnas.93.6.2464","volume":"93","author":"A Nagy","year":"1996","unstructured":"Nagy A, Armatis P, Schally AV. High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500\u20131000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin. Proc Natl Acad Sci. 1996;93:2464\u20139.","journal-title":"Proc Natl Acad Sci"},{"key":"2444_CR14","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1097\/01.cad.0000132231.28888.fa","volume":"15","author":"C Castex","year":"2004","unstructured":"Castex C, Merida P, Blanc E, Clair P, Rees AR, Temsamani J. 2-Pyrrolinodoxorubicin and its peptide-vectorized form bypass multidrug resistance. Anticancer Drugs. 2004;15:609\u201317.","journal-title":"Anticancer Drugs"},{"key":"2444_CR15","doi-asserted-by":"publisher","first-page":"7269","DOI":"10.1073\/pnas.93.14.7269","volume":"93","author":"A Nagy","year":"1996","unstructured":"Nagy A, Schally AV, Armatis P, Szepeshazi K, Halmos G, Kovacs M, et al. Cytotoxic analogs of luteinizing hormone-releasing hormone containing doxorubicin or 2-pyrrolinodoxorubicin, a derivative 500\u20131000 times more potent. Proc Natl Acad Sci USA. 1996;93:7269\u201373.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2444_CR16","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1073\/pnas.95.4.1794","volume":"95","author":"A Nagy","year":"1998","unstructured":"Nagy A, Schally AV, Halmos G, Armatis P, Cai R-Z, Csernus V, et al. Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin. Proc Natl Acad Sci. 1998;95:1794\u20139.","journal-title":"Proc Natl Acad Sci"},{"key":"2444_CR17","doi-asserted-by":"publisher","first-page":"5497","DOI":"10.1093\/emboj\/17.18.5497","volume":"17","author":"M Takata","year":"1998","unstructured":"Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, et al. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 1998;17:5497\u2013508.","journal-title":"EMBO J"},{"key":"2444_CR18","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/s13059-019-1867-0","volume":"20","author":"\u00c1 P\u00f3ti","year":"2019","unstructured":"P\u00f3ti \u00c1, Gyergy\u00e1k H, N\u00e9meth E, Rusz O, T\u00f3th S, Kov\u00e1csh\u00e1zi C, et al. Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. Genome Biol. 2019;20:240.","journal-title":"Genome Biol"},{"key":"2444_CR19","doi-asserted-by":"publisher","first-page":"1654","DOI":"10.1093\/emboj\/cdg161","volume":"22","author":"LJ Simpson","year":"2003","unstructured":"Simpson LJ, Sale JE. Rev1 is essential for DNA damage tolerance and non-templated Immunoglobulin gene mutation in a vertebrate cell line. EMBO J. 2003;22:1654\u201364.","journal-title":"EMBO J"},{"key":"2444_CR20","doi-asserted-by":"publisher","first-page":"1919","DOI":"10.3390\/cells12141919","volume":"12","author":"J T\u00f3v\u00e1ri","year":"2023","unstructured":"T\u00f3v\u00e1ri J, V\u00e1ri-Mez\u0151 D, Surguta SE, Lad\u00e1nyi A, Kigy\u00f3s A, Cserepes M. Evolving acquired Vemurafenib resistance in a BRAF V600E mutant melanoma PDTX model to reveal new potential targets. Cells. 2023;12:1919.","journal-title":"Cells"},{"key":"2444_CR21","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/newbio242148a0","volume":"242","author":"IJ Fidler","year":"1973","unstructured":"Fidler IJ. Selection of successive tumour lines for metastasis. Nat New Biology. 1973;242:148\u20139.","journal-title":"Nat New Biology"},{"key":"2444_CR22","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1038\/nmeth.4535","volume":"15","author":"AA Duarte","year":"2018","unstructured":"Duarte AA, Gogola E, Sachs N, Barazas M, Annunziato S, R de Ruiter J, et al. BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance. Nat Methods. 2018;15:134\u201340.","journal-title":"Nat Methods"},{"key":"2444_CR23","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1038\/s41592-019-0582-9","volume":"16","author":"S Berg","year":"2019","unstructured":"Berg S, Kutra D, Kroeger T, Straehle CN, Kausler BX, Haubold C, et al. Ilastik: interactive machine learning for (bio)image analysis. Nat Methods. 2019;16:1226\u201332.","journal-title":"Nat Methods"},{"key":"2444_CR24","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1186\/s12859-021-04344-9","volume":"22","author":"DR Stirling","year":"2021","unstructured":"Stirling DR, Swain-Bowden MJ, Lucas AM, Carpenter AE, Cimini BA, Goodman A. CellProfiler 4: improvements in speed, utility and usability. BMC Bioinformatics. 2021;22:433.","journal-title":"BMC Bioinformatics"},{"key":"2444_CR25","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1021\/ci500118s","volume":"54","author":"K Zhu","year":"2014","unstructured":"Zhu K, Borrelli KW, Greenwood JR, Day T, Abel R, Farid RS, et al. Docking covalent inhibitors: a parameter free approach to pose prediction and scoring. J Chem Inf Model. 2014;54:1932\u201340.","journal-title":"J Chem Inf Model"},{"key":"2444_CR26","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/nar\/28.1.235","volume":"28","author":"HM Berman","year":"2000","unstructured":"Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The protein data bank. Nucleic Acids Res. 2000;28:235\u201342.","journal-title":"Nucleic Acids Res"},{"key":"2444_CR27","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.1021\/acs.jcim.9b00843","volume":"60","author":"L Fusani","year":"2020","unstructured":"Fusani L, Palmer DS, Somers DO, Wall ID. Exploring ligand stability in protein crystal structures using binding pose metadynamics. J Chem Inf Model. 2020;60:1528\u201339.","journal-title":"J Chem Inf Model"},{"key":"2444_CR28","doi-asserted-by":"publisher","first-page":"2452","DOI":"10.1021\/jm970237e","volume":"40","author":"DJ Fenick","year":"1997","unstructured":"Fenick DJ, Taatjes DJ, Koch TH. Doxoform and daunoform: Anthracycline\u2009\u2013\u2009Formaldehyde conjugates toxic to resistant tumor cells. J Med Chem. 1997;40:2452\u201361.","journal-title":"J Med Chem"},{"key":"2444_CR29","doi-asserted-by":"publisher","first-page":"431","DOI":"10.2174\/1568011054866964","volume":"5","author":"SM Cutts","year":"2005","unstructured":"Cutts SM, Swift LP, Rephaeli A, Nudelman A, Phillips DR. Recent advances in Understanding and exploiting the activation of anthracyclines by formaldehyde. Curr Med Chem - Anti-Cancer Agents. 2005;5:431\u201347.","journal-title":"Curr Med Chem - Anti-Cancer Agents"},{"key":"2444_CR30","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.bcp.2011.04.010","volume":"82","author":"J Stepankova","year":"2011","unstructured":"Stepankova J, Studenovsky M, Malina J, Kasparkova J, Liskova B, Novakova O, et al. DNA interactions of 2-pyrrolinodoxorubicin, a distinctively more potent daunosamine-modified analogue of doxorubicin. Biochem Pharmacol. 2011;82:227\u201335.","journal-title":"Biochem Pharmacol"},{"key":"2444_CR31","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/nrc1951","volume":"6","author":"RH Shoemaker","year":"2006","unstructured":"Shoemaker RH. The NCI60 human tumour cell line anticancer drug screen. Nat Rev Cancer. 2006;6:813\u201323.","journal-title":"Nat Rev Cancer"},{"key":"2444_CR32","doi-asserted-by":"publisher","first-page":"e0171052","DOI":"10.1371\/journal.pone.0171052","volume":"12","author":"HP Varbanov","year":"2017","unstructured":"Varbanov HP, Kuttler F, Banfi D, Turcatti G, Dyson PJ. Repositioning approved drugs for the treatment of problematic cancers using a screening approach. PLoS ONE. 2017;12:e0171052.","journal-title":"PLoS ONE"},{"key":"2444_CR33","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/S0168-3659(97)00261-7","volume":"53","author":"A Gabizon","year":"1998","unstructured":"Gabizon A, Goren D, Cohen R, Barenholz Y. Development of liposomal anthracyclines: from basics to clinical applications. J Control Release. 1998;53:275\u20139.","journal-title":"J Control Release"},{"key":"2444_CR34","doi-asserted-by":"publisher","first-page":"111053","DOI":"10.1016\/j.colsurfb.2020.111053","volume":"192","author":"Z Varga","year":"2020","unstructured":"Varga Z, Feh\u00e9r B, Kitka D, Wacha A, B\u00f3ta A, Ber\u00e9nyi S, et al. Size measurement of extracellular vesicles and synthetic liposomes: the impact of the hydration shell and the protein Corona. Colloids Surf B Biointerfaces. 2020;192:111053.","journal-title":"Colloids Surf B Biointerfaces"},{"key":"2444_CR35","doi-asserted-by":"publisher","first-page":"466","DOI":"10.3390\/pharmaceutics12050466","volume":"12","author":"A Ga\u00e1l","year":"2020","unstructured":"Ga\u00e1l A, Garay TM, Horv\u00e1th I, M\u00e1th\u00e9 D, Sz\u00f6ll\u0151si D, Veres DS, et al. Development and in vivo application of a Water-Soluble anticancer copper ionophore system using a Temperature-Sensitive liposome formulation. Pharmaceutics. 2020;12:466.","journal-title":"Pharmaceutics"},{"key":"2444_CR36","first-page":"21","volume":"19","author":"L Serrone","year":"2000","unstructured":"Serrone L, Zeuli M, Sega FM, Cognetti F. Dacarbazine-based chemotherapy for metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res. 2000;19:21\u201334.","journal-title":"J Exp Clin Cancer Res"},{"key":"2444_CR37","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1093\/annonc\/mdl477","volume":"18","author":"D Lorusso","year":"2007","unstructured":"Lorusso D, Di Stefano A, Carone V, Fagotti A, Pisconti S, Scambia G. Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia (hand-foot syndrome). Ann Oncol. 2007;18:1159\u201364.","journal-title":"Ann Oncol"},{"key":"2444_CR38","doi-asserted-by":"publisher","first-page":"12111","DOI":"10.1073\/pnas.0702969104","volume":"104","author":"X Liu","year":"2007","unstructured":"Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci. 2007;104:12111\u20136.","journal-title":"Proc Natl Acad Sci"},{"key":"2444_CR39","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.drup.2007.11.002","volume":"11","author":"S Rottenberg","year":"2008","unstructured":"Rottenberg S, Jonkers J. Modeling therapy resistance in genetically engineered mouse cancer models. Drug Resist Updates. 2008;11:51\u201360.","journal-title":"Drug Resist Updates"},{"key":"2444_CR40","doi-asserted-by":"crossref","unstructured":"Rottenberg S, Nygren AOH, Pajic M, van Leeuwen FWB, van der Heijden I, van de Wetering K et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proceedings of the National Academy of Sciences. 2007;104:12117\u201322.","DOI":"10.1073\/pnas.0702955104"},{"key":"2444_CR41","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.jconrel.2017.07.010","volume":"261","author":"A F\u00fcredi","year":"2017","unstructured":"F\u00fcredi A, Szeb\u00e9nyi K, T\u00f3th S, Cserepes M, H\u00e1mori L, Nagy V, et al. Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer. J Controlled Release. 2017;261:287\u201396.","journal-title":"J Controlled Release"},{"key":"2444_CR42","doi-asserted-by":"publisher","first-page":"2026","DOI":"10.1007\/s00259-019-04589-w","volume":"47","author":"P Kannan","year":"2020","unstructured":"Kannan P, F\u00fcredi A, Dizdarevic S, Wanek T, Mairinger S, Collins J, et al. In vivo characterization of [18F]AVT-011 as a Radiotracer for PET imaging of multidrug resistance. Eur J Nucl Med Mol Imaging. 2020;47:2026\u201335.","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"2444_CR43","doi-asserted-by":"publisher","first-page":"116855","DOI":"10.1016\/j.bmc.2022.116855","volume":"67","author":"SP P\u00f3sa","year":"2022","unstructured":"P\u00f3sa SP, Darg\u00f3 G, Nagy S, Kissz\u00e9kelyi P, Gar\u00e1di Z, H\u00e1mori L, et al. Cytotoxicity of Cinchona alkaloid organocatalysts against MES-SA and MES-SA\/Dx5 multidrug-resistant uterine sarcoma cell lines. Bioorg Med Chem. 2022;67:116855.","journal-title":"Bioorg Med Chem"},{"key":"2444_CR44","first-page":"829","volume":"60","author":"F Arcamone","year":"1976","unstructured":"Arcamone F, Bernardi L, Giardino P, Patelli B, Marco A, Casazza AM, et al. Synthesis and antitumor activity of 4-demethoxydaunorubicin, 4-demethoxy-7,9-diepidaunorubicin, and their beta anomers. Cancer Treat Rep. 1976;60:829\u201334.","journal-title":"Cancer Treat Rep"},{"key":"2444_CR45","doi-asserted-by":"publisher","first-page":"788","DOI":"10.2165\/00003495-199345050-00011","volume":"45","author":"GL Plosker","year":"1993","unstructured":"Plosker GL, Faulds D, Epirubicin. A review of its pharmacodynamic and Pharmacokinetic properties, and therapeutic use in cancer chemotherapy. Drugs. 1993;45:788\u2013856.","journal-title":"Drugs"},{"key":"2444_CR46","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/s41568-020-00308-y","volume":"21","author":"S Rottenberg","year":"2021","unstructured":"Rottenberg S, Disler C, Perego P. The rediscovery of platinum-based cancer therapy. Nat Rev Cancer. 2021;21:37\u201350.","journal-title":"Nat Rev Cancer"},{"key":"2444_CR47","doi-asserted-by":"crossref","unstructured":"Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AOH, Zander SAL et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proceedings of the National Academy of Sciences. 2008;105:17079\u201384.","DOI":"10.1073\/pnas.0806092105"},{"key":"2444_CR48","doi-asserted-by":"publisher","first-page":"101007","DOI":"10.1016\/j.drup.2023.101007","volume":"71","author":"K Szeb\u00e9nyi","year":"2023","unstructured":"Szeb\u00e9nyi K, F\u00fcredi A, Bajtai E, Sama SN, Csiszar A, Gombos B, et al. Effective targeting of breast cancer by the Inhibition of P-glycoprotein mediated removal of toxic lipid peroxidation byproducts from drug tolerant persister cells. Drug Resist Updates. 2023;71:101007.","journal-title":"Drug Resist Updates"},{"key":"2444_CR49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41392-024-01891-4","volume":"9","author":"J He","year":"2024","unstructured":"He J, Qiu Z, Fan J, Xie X, Sheng Q, Sui X. Drug tolerant persister cell plasticity in cancer: a revolutionary strategy for more effective anticancer therapies. Sig Transduct Target Ther. 2024;9:1\u201324.","journal-title":"Sig Transduct Target Ther"},{"key":"2444_CR50","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/s12943-025-02310-0","volume":"24","author":"E Bajtai","year":"2025","unstructured":"Bajtai E, Kiss C, Bakos \u00c9, Lang\u00f3 T, Lovrics A, Sch\u00e1d \u00c9, et al. Therapy-induced senescence is a transient drug resistance mechanism in breast cancer. Mol Cancer. 2025;24:128.","journal-title":"Mol Cancer"},{"key":"2444_CR51","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1021\/bi00230a002","volume":"30","author":"AH Wang","year":"1991","unstructured":"Wang AH, Gao YG, Liaw YC, Li YK. Formaldehyde cross-links Daunorubicin and DNA efficiently: HPLC and X-ray diffraction studies. Biochemistry. 1991;30:3812\u20135.","journal-title":"Biochemistry"},{"key":"2444_CR52","doi-asserted-by":"publisher","first-page":"7648","DOI":"10.1021\/jm050678v","volume":"48","author":"GC Post","year":"2005","unstructured":"Post GC, Barthel BL, Burkhart DJ, Hagadorn JR, Koch TH. Doxazolidine, a proposed active metabolite of doxorubicin that Cross-links DNA. J Med Chem. 2005;48:7648\u201357.","journal-title":"J Med Chem"},{"key":"2444_CR53","doi-asserted-by":"publisher","first-page":"7020","DOI":"10.1158\/1078-0432.CCR-17-1279","volume":"23","author":"M Pajic","year":"2017","unstructured":"Pajic M, Blatter S, Guyader C, Gonggrijp M, Kersbergen A, K\u00fc\u00e7\u00fckosmano\u011flu A, et al. Selected alkylating agents can overcome drug tolerance of G0-like tumor cells and eradicate BRCA1-Deficient mammary tumors in mice. Clin Cancer Res. 2017;23:7020\u201333.","journal-title":"Clin Cancer Res"},{"key":"2444_CR54","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1016\/j.ijbiomac.2020.07.274","volume":"164","author":"M Alavi","year":"2020","unstructured":"Alavi M, Varma RS. Overview of novel strategies for the delivery of anthracyclines to cancer cells by liposomal and polymeric nanoformulations. Int J Biol Macromol. 2020;164:2197\u2013203.","journal-title":"Int J Biol Macromol"},{"key":"2444_CR55","doi-asserted-by":"publisher","first-page":"e000573","DOI":"10.1136\/bmjonc-2024-000573","volume":"4","author":"AA Gabizon","year":"2025","unstructured":"Gabizon AA, Gabizon-Peretz S, Modaresahmadi S, La-Beck NM. Thirty years from FDA approval of pegylated liposomal doxorubicin (Doxil\/Caelyx): an updated analysis and future perspective. BMJ Oncol. 2025;4:e000573.","journal-title":"BMJ Oncol"},{"key":"2444_CR56","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/j.nano.2016.07.012","volume":"13","author":"L Giodini","year":"2017","unstructured":"Giodini L, Re FL, Campagnol D, Marangon E, Posocco B, Dreussi E, et al. Nanocarriers in cancer clinical practice: a Pharmacokinetic issue. Nanomed Nanotechnol Biol Med. 2017;13:583\u201399.","journal-title":"Nanomed Nanotechnol Biol Med"},{"key":"2444_CR57","doi-asserted-by":"publisher","first-page":"115550","DOI":"10.1016\/j.addr.2025.115550","volume":"219","author":"IB Belyaev","year":"2025","unstructured":"Belyaev IB, Griaznova OYu, Yaremenko AV, Deyev SM, Zelepukin IV. Beyond the EPR effect: intravital microscopy analysis of nanoparticle drug delivery to tumors. Adv Drug Deliv Rev. 2025;219:115550.","journal-title":"Adv Drug Deliv Rev"}],"container-title":["Molecular Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12943-025-02444-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12943-025-02444-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12943-025-02444-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T12:04:27Z","timestamp":1761566667000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecular-cancer.biomedcentral.com\/articles\/10.1186\/s12943-025-02444-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["2444"],"URL":"https:\/\/doi.org\/10.1186\/s12943-025-02444-1","relation":{},"ISSN":["1476-4598"],"issn-type":[{"value":"1476-4598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,27]]},"assertion":[{"value":"31 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Animal protocols were approved by the Hungarian Animal Health and Animal Welfare Directorate according to the EU\u2019s most recent directives. All surgical procedures were performed according to the Committee on the Care and Use of Laboratory Animals of the Council on Animal Care at the Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary (PEI\/001\/1738-3\/2015 and PE\/EA\/1461-7\/2020).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"269"}}