期刊
ACS NANO
卷 13, 期 11, 页码 12511-12524出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.9b02875
关键词
quercetin; alantolactone; immunogenic cell death; micelle; tumor microenvironment
类别
资金
- NIH [CA198999]
- National Natural Science Foundation of China [81560575, 81760639, 81603054]
- Jiangxi Province Outstanding Young Talents Program [20162BCB23034, 20171BCB23097]
- Young Jinggang Scholar of Jiangxi Province [[2018]82, [2018]42]
- 1050 Talents Program [[2018]82, [2018]42]
- Jiangxi BaiQianWan Talents Program [2017082]
- Natural Science Fund of Jiangxi Province [20171BAB215066, 20171ACB21074]
- Fund for FirstRate Discipline of Chinese Materia Medica [JXSYLXKZHYA0055, JXSYLXK-ZHYA0056, JXSYLXK-ZHYA0019]
- China Postdoctoral Science Foundation [2016M602084]
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.
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