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We developed an in vitro multiparametric model using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to assess the relative toxicity of anthracyclines across formulations. Proof of concept was established by treating hiPSC-CM with equivalent concentrations of free and liposomal doxorubicin. The study was then repeated with free daunorubicin plus cytarabine and CPX-351, a dual-drug liposomal encapsulation of daunorubicin\/cytarabine. hiPSC-CM were treated with free-drug or liposomal formulations for 24\u00a0h on Days 1, 3, and 5 at equivalent concentrations ranging from 0 to 1000\u00a0ng\/mL and assessed on subsequent days. Free-drug treatment resulted in concentration-dependent cumulative cytotoxicity (microscopy), more profound decrease in ATP levels, and significant time- and concentration-dependent decreases in oxygen consumption versus liposomal formulations (p\u2009&lt;\u20090.01). Repeated free-drug exposure also resulted in greater release of biomarkers (cardiac troponin I, FABP3) and lactate dehydrogenase, as well as in a biphasic rhythmicity response (initial increase followed by slowing\/quiescence of beating) indicating significant injury, which was not observed after repeated exposure to liposomal formulations. Overall, liposomal formulations were considerably less toxic to hiPSC-CM than their free-drug counterparts. Clinical data will be needed to confirm findings for CPX-351.<\/jats:p>","DOI":"10.1038\/s41598-023-47293-4","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T15:02:21Z","timestamp":1701270141000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Lower cardiotoxicity of CPX-351 relative to daunorubicin plus cytarabine free-drug combination in hiPSC-derived cardiomyocytes in vitro"],"prefix":"10.1038","volume":"13","author":[{"given":"Marie C.","family":"Fortin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew S.","family":"LaCroix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom N.","family":"Grammatopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dino","family":"Manca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"47293_CR1","doi-asserted-by":"crossref","unstructured":"World Health Organization. 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QW is a former employee of and holds stock in Jazz Pharmaceuticals. AL is an employee of StemoniX, and TNG is an employee of BioEnergetics LLC, both of whom were contracted by Jazz Pharmaceuticals for the conduct of this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"21054"}}