Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Signal Transduction and Targeted Therapy Pub Date : 2024-10-14 DOI:10.1038/s41392-024-01973-3
Yu Xiao, Tao Pan, Wuren Da, Yuanding Liu, Shuangya Chen, Daiquan Chen, Keying Liu, Yihan Zheng, Daolong Xie, Yuan Gao, Haiyan Xu, Yang Sun, Weihong Tan
{"title":"Aptamer-drug conjugates-loaded bacteria for pancreatic cancer synergistic therapy","authors":"Yu Xiao, Tao Pan, Wuren Da, Yuanding Liu, Shuangya Chen, Daiquan Chen, Keying Liu, Yihan Zheng, Daolong Xie, Yuan Gao, Haiyan Xu, Yang Sun, Weihong Tan","doi":"10.1038/s41392-024-01973-3","DOIUrl":null,"url":null,"abstract":"<p>Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of <i>Salmonella typhimurium</i>, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer’s specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer’s targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":40.8000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Signal Transduction and Targeted Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41392-024-01973-3","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Pancreatic cancer is one of the most malignant tumors with the highest mortality rates, and it currently lacks effective drugs. Aptamer-drug conjugates (ApDC), as a form of nucleic acid drug, show great potential in cancer therapy. However, the instability of nucleic acid-based drugs in vivo and the avascularity of pancreatic cancer with dense stroma have limited their application. Fortunately, VNP20009, a genetically modified strain of Salmonella typhimurium, which has a preference for anaerobic environments, but is toxic and lacks specificity, can potentially serve as a delivery vehicle for ApDC. Here, we propose a synergistic therapy approach that combines the penetrative capability of bacteria with the targeting and toxic effects of ApDC by conjugating ApDC to VNP20009 through straightforward, one-step click chemistry. With this strategy, bacteria specifically target pancreatic cancer through anaerobic chemotaxis and subsequently adhere to tumor cells driven by the aptamer’s specific binding. Results indicate that this method prolongs the serum stability of ApDC up to 48 h and resulted in increased drug concentration at tumor sites compared to the free drugs group. Moreover, the aptamer’s targeted binding to cancer cells tripled bacterial colonization at the tumor site, leading to increased death of tumor cells and T cell infiltration. Notably, by integrating chemotherapy and immunotherapy, the effectiveness of the treatment is significantly enhanced, showing consistent results across various animal models. Overall, this strategy takes advantage of bacteria and ApDC and thus presents an effective synergistic strategy for pancreatic cancer treatment.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
用于胰腺癌协同治疗的载药链烷共轭细菌
胰腺癌是死亡率最高的恶性肿瘤之一,目前缺乏有效的治疗药物。作为核酸药物的一种形式,色聚体-药物共轭物(ApDC)在癌症治疗中显示出巨大的潜力。然而,核酸类药物在体内的不稳定性以及胰腺癌的无血管性和致密基质限制了其应用。幸运的是,VNP20009 是一种转基因鼠伤寒沙门氏菌菌株,它偏好厌氧环境,但具有毒性且缺乏特异性,有可能成为 ApDC 的递送载体。在这里,我们提出了一种协同治疗方法,通过简单的一步点击化学反应将 ApDC 与 VNP20009 连接,将细菌的穿透能力与 ApDC 的靶向性和毒性作用结合起来。利用这种策略,细菌通过厌氧趋化作用特异性地靶向胰腺癌,随后在aptamer的特异性结合作用下粘附到肿瘤细胞上。结果表明,与游离药物组相比,这种方法可将 ApDC 的血清稳定性延长至 48 小时,并提高了药物在肿瘤部位的浓度。此外,适配体与癌细胞的靶向结合使肿瘤部位的细菌定植增加了两倍,导致肿瘤细胞死亡和 T 细胞浸润增加。值得注意的是,通过整合化疗和免疫疗法,治疗效果显著增强,在各种动物模型中显示出一致的结果。总之,这种策略利用了细菌和 ApDC 的优势,从而为胰腺癌治疗提供了一种有效的协同策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
期刊最新文献
Overexpression of STX11 alleviates pulmonary fibrosis by inhibiting fibroblast activation via the PI3K/AKT/mTOR pathway Post-fast refeeding: rise of intestinal stemness and mutagen-induced cancer risk through polyamine metabolism Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization First-line benmelstobart plus anlotinib and chemotherapy in advanced or metastatic/recurrent esophageal squamous cell carcinoma: a multi-center phase 2 study Moving towards precision psychiatry: the hard nut of depression
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1