{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:48:22Z","timestamp":1789465702514,"version":"build-2803163510"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007620","name":"Scientific Research Fund of Liaoning Province Education Administration","doi-asserted-by":"publisher","award":["JYTMS20230567"],"award-info":[{"award-number":["JYTMS20230567"]}],"id":[{"id":"10.13039\/501100007620","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007620","name":"Scientific Research Fund of Liaoning Province Education Administration","doi-asserted-by":"publisher","award":["L1212410161013"],"award-info":[{"award-number":["L1212410161013"]}],"id":[{"id":"10.13039\/501100007620","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: combination chemotherapy employing agents with complementary mechanisms of action can enhance therapeutic efficacy and overcome resistance, but mismatched pharmacokinetics and systemic toxicity limit benefit. Methods: We designed reductant-responsive squalene prodrugs of doxorubicin (DOX) and exatecan (EXA) that co-assemble with DSPE-PEG2k into approximately 76 nm dual-prodrug nanoparticles (doxorubicin prodrug\u2013exatecan prodrug nanoparticles, DP-EP NPs) at a predefined synergistic ratio 1:2. Results: The minimalist, drug-as-carrier formulation achieved high effective loadings with minimal leakage under normoxia, yet synchronously liberated both drugs in reductive, hypoxia-mimicking media (24 h release: DOX ~65% and EXA ~58% at 1 mM Na2S2O4 vs. ~8\u201311% at 0 mM Na2S2O4). In MCF-7 and 4T1 cells, the nanoparticles enhanced intracellular accumulation, intensified the disruption of DNA damage repair, as evidenced by increased colocalization of 53BP1 and enhanced \u03b3-H2AX foci, and induced markers of immunogenic cell death, including increased CRT-associated cellular fluorescence and reduced intracellular HMGB1 staining. Furthermore, they partially reversed drug resistance in MCF-7\/ADR cells. In rats, the formulation prolonged circulation and increased exposure (DOX t\u00bd ~9\u00d7, AUC ~1.8\u00d7; EXA t\u00bd ~5\u00d7, AUC ~14.9\u00d7) relative to the free-drug mixture. In 4T1 tumor-bearing mice, the nanoparticles produced the greatest tumor-growth inhibition with improved tolerability, supported by stable body weight and benign histopathology. Conclusions: These findings establish a scalable, excipient-lean platform that aligns pharmacokinetics with microenvironment-triggered pharmacodynamics to deliver synchronized Topo II\/I inhibition for synergistic chemotherapy.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091155","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:16:48Z","timestamp":1789460208000},"page":"1155","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reductant-Responsive Squalene Dual-Prodrug Nanoparticles Co-Delivering Doxorubicin and Exatecan for Synergistic Breast Tumor Therapy"],"prefix":"10.3390","volume":"18","author":[{"given":"Li","family":"Wang","sequence":"first","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Ning","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yina","family":"Sa","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Zhenghua","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Yanlong","family":"Qiao","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Lixue","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Xiangyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Day Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian 116021, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Dalian Medical University, Dalian 116044, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jconrel.2017.05.023","article-title":"Advances in combination therapy of lung cancer: Rationales, delivery technologies and dosage regimens","volume":"260","author":"Wu","year":"2017","journal-title":"J. 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