Jiahao Liu, Long Wang, Yongbo Peng, Shuyang Long, Hongliang Zeng, Minhua Deng, Wei Xiang, Biao Liu, Xing Hu, Xuewen Liu, Jianfei Xie, Weibin Hou, Jin Tang, Jianye Liu
{"title":"A novel therapeutic strategy utilizing EpCAM aptamer-conjugated gemcitabine for targeting bladder cancer and cancer stem cells.","authors":"Jiahao Liu, Long Wang, Yongbo Peng, Shuyang Long, Hongliang Zeng, Minhua Deng, Wei Xiang, Biao Liu, Xing Hu, Xuewen Liu, Jianfei Xie, Weibin Hou, Jin Tang, Jianye Liu","doi":"10.1039/d4bm01471e","DOIUrl":null,"url":null,"abstract":"<p><p>Gemcitabine (GEM) is a first line chemotherapy drug for bladder cancer (BCa). GEM's lack of specificity has led to disadvantages, resulting in low efficiency, especially when combined with the targeted treatment of BCa stem cells (CSCs), which is considered the cause of BCa recurrence and progression. To enhance the anti-cancer effect and reduce the side effects of GEM targeting of BCa cells/CSCs, an aptamer drug conjugate (ApDC) targeted delivery system was used to improve the efficiency of GEM in BCa therapy using EpCAM aptamer-GEM conjugates based on the epithelial cell adhesion molecule (EpCAM), which is highly expressed on the cell membrane of BCa cells/CSCs. We designed and synthesized EpCAM aptamer gemcitabine conjugates (EpCAM-GEMs, one aptamer carried three GEMs). The targeting effect of EpCAM-GEMs was examined in a xenograft model using an <i>in vivo</i> imaging system. To evaluate the antitumor activity and mechanism of EpCAM-GEMs, Cell Counting Kit-8, apoptosis and colony formation assays; BCa CSC xenotransplantation; xenotransplantation of subcutaneous tumors; a lung metastasis model; an <i>in situ</i> model; and biosafety assessment were used <i>in vitro</i> and <i>in vivo</i>. EpCAM is highly expressed on the surface of BCa cells/CSCs. EpCAM-GEMs were automatically synthesized using a DNA synthesizer, were stable in serum, and selectively delivered GEM to kill BCa cells/CSCs. EpCAM-GEMs entered BCa cells <i>via</i> macropinocytosis, released GEM to inhibit DNA synthesis, and degraded all BCa cells under the action of a BCa cell intracellular phosphatase; however, they did not kill normal cells because of their low EpCAM expression. EpCAM-GEMs inhibited BCa growth and metastasis in three bladder tumor models, with good biosafety. These results demonstrated the targeted anti-tumor efficiency and good biosafety of EpCAM-GEMs in BCa treatment, which will provide a new therapeutic strategy in BCa biomarker targeted therapy.</p>","PeriodicalId":65,"journal":{"name":"Biomaterials Science","volume":" ","pages":""},"PeriodicalIF":5.8000,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomaterials Science","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1039/d4bm01471e","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MATERIALS SCIENCE, BIOMATERIALS","Score":null,"Total":0}
引用次数: 0
Abstract
Gemcitabine (GEM) is a first line chemotherapy drug for bladder cancer (BCa). GEM's lack of specificity has led to disadvantages, resulting in low efficiency, especially when combined with the targeted treatment of BCa stem cells (CSCs), which is considered the cause of BCa recurrence and progression. To enhance the anti-cancer effect and reduce the side effects of GEM targeting of BCa cells/CSCs, an aptamer drug conjugate (ApDC) targeted delivery system was used to improve the efficiency of GEM in BCa therapy using EpCAM aptamer-GEM conjugates based on the epithelial cell adhesion molecule (EpCAM), which is highly expressed on the cell membrane of BCa cells/CSCs. We designed and synthesized EpCAM aptamer gemcitabine conjugates (EpCAM-GEMs, one aptamer carried three GEMs). The targeting effect of EpCAM-GEMs was examined in a xenograft model using an in vivo imaging system. To evaluate the antitumor activity and mechanism of EpCAM-GEMs, Cell Counting Kit-8, apoptosis and colony formation assays; BCa CSC xenotransplantation; xenotransplantation of subcutaneous tumors; a lung metastasis model; an in situ model; and biosafety assessment were used in vitro and in vivo. EpCAM is highly expressed on the surface of BCa cells/CSCs. EpCAM-GEMs were automatically synthesized using a DNA synthesizer, were stable in serum, and selectively delivered GEM to kill BCa cells/CSCs. EpCAM-GEMs entered BCa cells via macropinocytosis, released GEM to inhibit DNA synthesis, and degraded all BCa cells under the action of a BCa cell intracellular phosphatase; however, they did not kill normal cells because of their low EpCAM expression. EpCAM-GEMs inhibited BCa growth and metastasis in three bladder tumor models, with good biosafety. These results demonstrated the targeted anti-tumor efficiency and good biosafety of EpCAM-GEMs in BCa treatment, which will provide a new therapeutic strategy in BCa biomarker targeted therapy.
期刊介绍：
Biomaterials Science is an international high impact journal exploring the science of biomaterials and their translation towards clinical use. Its scope encompasses new concepts in biomaterials design, studies into the interaction of biomaterials with the body, and the use of materials to answer fundamental biological questions.
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