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

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.