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

作　　者：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 

机构地区：[1]Institute of Molecular Medicine(IMM),State Key Laboratory of Oncogenes and Related Genes,Shanghai Cancer Institute,Department of Oncology,Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai,China [2]Zhejiang Cancer Hospital,Hangzhou Institute of Medicine(HIM),Chinese Academy of Sciences,Hangzhou,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第11期5200-5216,共17页信号转导与靶向治疗（英文）

基　　金：the China Postdoctoral Science Foundation(Certificate Number:2023M742348);the Fundamental Research Funds for the Central Universities(2020JCPT02);the“Innovation Research Team of High-Level of Local Universities in Shanghai”;the National Key Research and Development Program of China(2023YFC3405100).

摘　　要：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.

关 键 词：DRUGS SPECIFICITY SYNERGISTIC 

分 类 号：R735.9[医药卫生—肿瘤]