A ROS-Responsive Aspirin Polymeric Prodrug for Modulation of Tumor Microenvironment and Cancer Immunotherapy  

作　　者：Sheng Ma Wantong Song Yudi Xu Xinghui Si Yu Zhang Zhaohui Tang Xuesi Chen 

机构地区：[1]Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022 [2]University of Science and Technology of China,Hefei 230026 [3]Jilin Biomedical Polymers Engineering Laboratory,Changchun 130022 [4]State Key Laboratory of Molecular Engineering of Polymers(Fudan University),Shanghai 200433 [5]University of Chinese Academy of Sciences,Beijing 100039

出　　处：《CCS Chemistry》2020年第6期390-400,共11页中国化学会会刊（英文）

基　　金：supported by the National Natural Science Foundation of China(51673185,51973215,51673189,51833010,51829302,and 51520105004);the Jilin Province Science and Technology Development Plan(20170101100JC and 20190103112JH);Ministry of Science and Technology of China(2016YFC1100701).

摘　　要：Tumor-promoting inflammation is accompanied by cancer initiation,progression,and metastasis.Cyclooxygenase-2(COX-2)and its downstream product,prostaglandin E2(PGE2),play critical roles in tumor-promoting inflammation.Several studies have revealed the potential of COX-2 inhibition in improving cancer response to chemotherapy,as well as immunotherapy.Aspirin,a nonsteroidal anti-inflammatory drug,has been reported as a COX-2 inhibitor.However,as a small molecule drug with a carboxyl group,there is still the lack of effective methods of preparing polymer–aspirin conjugates with tumor stimuli-responsive release properties.Herein,we synthesized a reactive oxygen species(ROS)-responsive aspirin polymeric prodrug(P3C-Asp)via Passerini three-component reaction between aspirin,4-formylbenzeneboronic acid pinacol ester,and 5-isocyanopent-1-yne,followed by copper(I)-catalyzed alkyne-azide cycloaddition“click”reaction of the aspirin prodrug with dextran(DEX).The P3C-Asp could release aspirin and salicylic acid in response to tumor-specific stimuli.In the murine colorectal cancer model,P3C-Asp suppressed tumor growth effectively without significant side effects and eradicated tumors when combined with the immune checkpoint inhibitor,anti-PD-1 antibody(aPD-1).Further analysis revealed that the suppression was attributable to changes in the immune microenvironment,including reduced PGE2 content,as well as increased infiltration of CD8+T cells and M1 macrophages.The results mentioned above proved that targeting COX-2 pathway with a proper polymeric prodrug might be a useful strategy for cancer immunotherapy.

关 键 词：COX-2 ASPIRIN polymeric prodrug tumor microenvironment cancer immunotherapy 

分 类 号：R730.51[医药卫生—肿瘤]