Nanoformulated Codelivery of Quercetin and Alantolactone Promotes an Antitumor Response through Synergistic Immunogenic Cell Death for Microsatellite-Stable Colorectal Cancer

Microsatellite-stable colorectal cancer (CRC) is known to be resistant to immunotherapy. The combination of quercetin (Q) and alantolactone (A) was found to induce synergistic immunogenic cell death (ICD) at a molar ratio of 1:4 (Q:A). To achieve ratiometric loading and delivery, the micellar delivery of Q and A (QA-M) was developed with high entrapment efficiency and drug loading at an optimal ratio. QA-M achieved prolonged blood circulation and increased tumor accumulation for both drugs. More importantly, QA-M retained the desired drug ratio (molar ratio of Q to A = 1:4) in tumors at 2 and 4 h after intravenous injection for synergistic immunotherapy. Tumor growth was significantly inhibited in murine orthotopic CRC by the treatment of QA-M compared to PBS and the combination of free drugs (p < 0.005). The combination of nanotherapy stimulated the host immune response to induce long-term tumor destruction and induced memory tumor surveillance with a 1.3-fold increase in survival median time compared to PBS (p < 0.0001) and a combination of free drugs (p < 0.0005). The synergistic therapeutic effect induced by codelivery of Q and A is capable of reactivating antitumor immunity by inducing ICD, causing cell toxicity and modulating the immune-suppressive tumor microenvironment. Such a combination of Q and A with synergistic effects entrapped in a simple and safe nanodelivery system may provide the potential for scale-up manufacturing and clinical applications as immunotherapeutic agents for CRC.