{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:41:14Z","timestamp":1785904874220,"version":"3.56.0"},"reference-count":28,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81773643"],"award-info":[{"award-number":["81773643"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Start-Up Fund for Excellent Talents of Xuzhou Medical University","award":["D2021055"],"award-info":[{"award-number":["D2021055"]}]},{"name":"Central Public Welfare Research Institutes","award":["ZZ18-YQ-050"],"award-info":[{"award-number":["ZZ18-YQ-050"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Objectives: This study developed pH\/enzyme-sensitive polymeric HA-AAN-DOX (HAD) micelles to resolve the limited targeting specificity of chemotherapy drugs. Methods: Hyaluronic acid (HA) and the chemotherapeutic agent doxorubicin (DOX) were conjugated via a hydrazone linkage utilizing an Ala-Ala-ASP tripeptide (AAN) as the connecting moiety, which is sensitive to the legumain enzyme. DOX was delivered via HAD micelles, which were activated by both hyaluronidase and the legumain enzyme. Key findings: The results revealed the remarkable antitumor efficacy of these micelles both in vivo and in vitro. Compared with that of doxorubicin hydrochloride (DOX\u00b7HCl), the incidence of toxic side effects was significantly reduced with the HAD micelle treatment. As a result, micelles composed of hyaluronic acid and doxorubicin (HAD) offer a reliable and effective method for drug delivery, with the potential to optimize the therapeutic impact of chemotherapeutic agents on tumors by reducing unintended side effects. Conclusions: Micelles composed of hyaluronic acid and doxorubicin (HAD) offer a reliable and effective method for drug delivery, with the potential to optimize the therapeutic impact of chemotherapeutic agents on tumors by reducing unintended side effects.<\/jats:p>","DOI":"10.3390\/molecules31050851","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T16:17:31Z","timestamp":1772641051000},"page":"851","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A pH\/Enzyme-Sensitive Doxorubicin Prodrug Micelle for Safe and Effective Cancer Treatment"],"prefix":"10.3390","volume":"31","author":[{"given":"Xiang","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing 100875, China"},{"name":"State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University College of Pharmacy, Yanji 133002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyue","family":"Wu","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China"},{"name":"Department of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Na","sequence":"additional","affiliation":[{"name":"Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing 100875, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Yang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China"},{"name":"Department of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongcheng","family":"Yi","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China"},{"name":"Department of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China"},{"name":"Department of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China"},{"name":"Department of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China"},{"name":"Department of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yabing","family":"Hua","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China"},{"name":"Department of Pharmacy, Xuzhou Medical University, Xuzhou 221004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"28254","DOI":"10.1021\/acsami.9b04735","article-title":"Platelet-Membrane-Camouflaged Black Phosphorus Quantum Dots Enhance Anticancer Effect Mediated by Apoptosis and Autophagy","volume":"11","author":"Shang","year":"2019","journal-title":"ACS Appl. 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