1. Nanoformulated Codelivery of Quercetin and Alantolactone Promotes an Antitumor Response through Synergistic Immunogenic Cell Death for Microsatellite-Stable Colorectal Cancer.
- Author
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Zhang J, Shen L, Li X, Song W, Liu Y, and Huang L
- Subjects
- Animals, Apoptosis drug effects, Colorectal Neoplasms genetics, Drug Delivery Systems, Drug Synergism, Female, Mice, Mice, Inbred BALB C, Micelles, Microsatellite Repeats genetics, Tumor Microenvironment drug effects, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Colorectal Neoplasms metabolism, Lactones chemistry, Lactones pharmacokinetics, Lactones pharmacology, Nanoparticles chemistry, Nanoparticles metabolism, Quercetin chemistry, Quercetin pharmacokinetics, Quercetin pharmacology, Sesquiterpenes, Eudesmane chemistry, Sesquiterpenes, Eudesmane pharmacokinetics, Sesquiterpenes, Eudesmane pharmacology
- Abstract
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.
- Published
- 2019
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