{"title":"合理设计一种基于聚 L-谷氨酸的组合共轭物,用于治疗激素反应性乳腺癌。","authors":"","doi":"10.1016/j.jconrel.2024.09.002","DOIUrl":null,"url":null,"abstract":"<div><p>Breast cancer represents the most prevalent tumor type worldwide, with hormone-responsive breast cancer the most common subtype. Despite the effectiveness of endocrine therapy, advanced disease forms represent an unmet clinical need. While drug combination therapies remain promising, differences in pharmacokinetic profiles result in suboptimal ratios of free drugs reaching tumors. We identified a synergistic combination of bisdemethoxycurcumin and exemestane through drug screening and rationally designed <em>star</em>-shaped poly-L-glutamic acid-based combination conjugates carrying these drugs conjugated through pH-responsive linkers for hormone-responsive breast cancer treatment. We synthesized/characterized single and combination conjugates with synergistic drug ratios/loadings. Physicochemical characterization/drug release kinetics studies suggested that lower drug loading prompted a less compact conjugate conformation that supported optimal release. Screening in monolayer and spheroid breast cancer cell cultures revealed that combination conjugates possessed enhanced cytotoxicity/synergism compared to physical mixtures of single-drug conjugates/free drugs; moreover, a combination conjugate with the lowest drug loading outperformed remaining conjugates. This candidate inhibited proliferation-associated signaling, reduced inflammatory chemokine/exosome levels, and promoted autophagy in spheroids; furthermore, it outperformed a physical mixture of single-drug conjugates/free drugs regarding cytotoxicity in patient-derived breast cancer organoids. Our findings highlight the importance of rational design and advanced in vitro models for the selection of polypeptide-based combination conjugates.</p></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":null,"pages":null},"PeriodicalIF":10.5000,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0168365924006047/pdfft?md5=6462850149337601a730fb9d392d0810&pid=1-s2.0-S0168365924006047-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Rational design of a poly-L-glutamic acid-based combination conjugate for hormone-responsive breast cancer treatment\",\"authors\":\"\",\"doi\":\"10.1016/j.jconrel.2024.09.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Breast cancer represents the most prevalent tumor type worldwide, with hormone-responsive breast cancer the most common subtype. Despite the effectiveness of endocrine therapy, advanced disease forms represent an unmet clinical need. While drug combination therapies remain promising, differences in pharmacokinetic profiles result in suboptimal ratios of free drugs reaching tumors. We identified a synergistic combination of bisdemethoxycurcumin and exemestane through drug screening and rationally designed <em>star</em>-shaped poly-L-glutamic acid-based combination conjugates carrying these drugs conjugated through pH-responsive linkers for hormone-responsive breast cancer treatment. We synthesized/characterized single and combination conjugates with synergistic drug ratios/loadings. Physicochemical characterization/drug release kinetics studies suggested that lower drug loading prompted a less compact conjugate conformation that supported optimal release. Screening in monolayer and spheroid breast cancer cell cultures revealed that combination conjugates possessed enhanced cytotoxicity/synergism compared to physical mixtures of single-drug conjugates/free drugs; moreover, a combination conjugate with the lowest drug loading outperformed remaining conjugates. This candidate inhibited proliferation-associated signaling, reduced inflammatory chemokine/exosome levels, and promoted autophagy in spheroids; furthermore, it outperformed a physical mixture of single-drug conjugates/free drugs regarding cytotoxicity in patient-derived breast cancer organoids. Our findings highlight the importance of rational design and advanced in vitro models for the selection of polypeptide-based combination conjugates.</p></div>\",\"PeriodicalId\":15450,\"journal\":{\"name\":\"Journal of Controlled Release\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":10.5000,\"publicationDate\":\"2024-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0168365924006047/pdfft?md5=6462850149337601a730fb9d392d0810&pid=1-s2.0-S0168365924006047-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Controlled Release\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0168365924006047\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Controlled Release","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0168365924006047","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Rational design of a poly-L-glutamic acid-based combination conjugate for hormone-responsive breast cancer treatment
Breast cancer represents the most prevalent tumor type worldwide, with hormone-responsive breast cancer the most common subtype. Despite the effectiveness of endocrine therapy, advanced disease forms represent an unmet clinical need. While drug combination therapies remain promising, differences in pharmacokinetic profiles result in suboptimal ratios of free drugs reaching tumors. We identified a synergistic combination of bisdemethoxycurcumin and exemestane through drug screening and rationally designed star-shaped poly-L-glutamic acid-based combination conjugates carrying these drugs conjugated through pH-responsive linkers for hormone-responsive breast cancer treatment. We synthesized/characterized single and combination conjugates with synergistic drug ratios/loadings. Physicochemical characterization/drug release kinetics studies suggested that lower drug loading prompted a less compact conjugate conformation that supported optimal release. Screening in monolayer and spheroid breast cancer cell cultures revealed that combination conjugates possessed enhanced cytotoxicity/synergism compared to physical mixtures of single-drug conjugates/free drugs; moreover, a combination conjugate with the lowest drug loading outperformed remaining conjugates. This candidate inhibited proliferation-associated signaling, reduced inflammatory chemokine/exosome levels, and promoted autophagy in spheroids; furthermore, it outperformed a physical mixture of single-drug conjugates/free drugs regarding cytotoxicity in patient-derived breast cancer organoids. Our findings highlight the importance of rational design and advanced in vitro models for the selection of polypeptide-based combination conjugates.
期刊介绍:
The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System.
Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries.
Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.