Nanoformulated Codelivery of Quercetin and Alantolactone Promotes an Antitumor Response through Synergistic Immunogenic Cell Death for Microsatellite-Stable Colorectal Cancer.
Nanoformulated Codelivery of Quercetin and Alantolactone Promotes an Antitumor Response through Synergistic Immunogenic Cell Death for Microsatellite-Stable Colorectal Cancer.
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DOI：
10.1021/acsnano.9b02875
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发表时间：
2019-10
期刊：
影响因子：
17.1
通讯作者：
Jing Zhang;Limei Shen;Xiang Li;Wantong Song;Yun Liu;Leaf Huang
中科院分区：
文献类型：
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作者：
Jing Zhang;Limei Shen;Xiang Li;Wantong Song;Yun Liu;Leaf Huang
已知微卫星稳定的结直肠癌（CRC）对免疫疗法具有抗性。发现槲皮素（Q）和土木香内酯（A）的组合以1：4（Q：A）的摩尔比诱导协同免疫原性细胞死亡（ICD）。为了实现成比例的载药和释放，开发了具有高包封率和最佳载药量比的Q和A胶束释放（QA-M）。QA-M延长了血液循环，增加了两种药物的肿瘤蓄积。更重要的是，QA-M在静脉注射用于协同免疫治疗后2和4小时在肿瘤中保留了所需的药物比例（Q与A的摩尔比= 1：4）。与PBS和游离药物的组合相比，通过QA-M处理，在鼠原位CRC中肿瘤生长被显著抑制（p<0.005）。与PBS（p<0.0001）和游离药物组合（p<0.0005）相比，纳米疗法的组合刺激宿主免疫应答以诱导长期肿瘤破坏并诱导记忆肿瘤监视，其中存活中位时间增加1.3倍。Q和A共递送诱导的协同治疗作用能够通过诱导ICD、引起细胞毒性和调节免疫抑制性肿瘤微环境来重新激活抗肿瘤免疫。这种Q和A的组合与捕获在一个简单和安全的纳米递送系统中的协同效应，可以提供作为CRC的免疫抑制剂的规模化生产和临床应用的潜力。
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 are 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.