Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment
Binary Cooperative Prodrug Nanoparticles Improve Immunotherapy by Synergistically Modulating Immune Tumor Microenvironment
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二元协同前药纳米颗粒通过协同调节免疫肿瘤微环境改善免疫治疗
DOI：
10.1002/adma.201803001
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发表时间：
2018-09-20
影响因子：
29.4
通讯作者：
Li, Yaping
中科院分区：
文献类型：
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作者：
Feng, Bing;Zhou, Fangyuan;Li, Yaping
检查点阻断免疫治疗有望用于各种恶性肿瘤的临床治疗。然而，由于肿瘤免疫原性不足和免疫抑制性肿瘤微环境（ITM），检查点阻断免疫疗法的应答率较低。在这项研究中，合理设计了一种可激活肿瘤微环境的二元协同前药纳米颗粒（BCPN），通过协同调节免疫肿瘤微环境来改善免疫治疗。BCPN完全由肿瘤酸性和还原双重响应的奥沙利铂（OXA）前药和NLG 919的还原可激活同型二聚体构建，前者用于触发免疫原性细胞死亡（ICD）和引发抗肿瘤免疫，后者用于灭活吲哚胺2，3-双加氧酶1，这是ITM的关键调节因子。在肿瘤酸性触发的聚（乙二醇）壳裂解后，PN显示负电荷至正电荷的转换，以增强肿瘤蓄积和深度渗透。然后，OXA和NLG 919通过谷胱甘肽介导的还原在肿瘤细胞中被激活。研究表明，活化的OXA通过触发癌细胞的ICD促进细胞毒性T淋巴细胞的肿瘤内积聚。同时，NLG 919下调IDO-1介导的免疫抑制并抑制调节性T细胞。最重要的是，PN显示出比游离OXA或游离OXA和NLG 919的组合高得多的效率，以使乳腺癌和结肠直肠癌的小鼠模型的肿瘤生长消退并预防转移。
Checkpoint blockade immunotherapy is promising for clinical treatment of various malignant tumors. However, checkpoint blockade immunotherapy suffers from a low response rate due to insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment (ITM). In this study, a tumor‐microenvironment‐activatable binary cooperative prodrug nanoparticle (BCPN) is rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. BCPN is purely constructed from a tumor acidity and reduction dual‐responsive oxaliplatin (OXA) prodrug for triggering immunogenic cell death (ICD) and eliciting antitumor immunity, and a reduction‐activatable homodimer of NLG919 for inactivating indoleamine 2,3‐dioxygenase 1, which is a key regulator for ITM. Upon tumor‐acidity‐triggered cleavage of the poly(ethylene glycol) shell, PN shows negative to positive charge switch for enhanced tumor accumulation and deep penetration. OXA and NLG919 are then activated in the tumor cells via glutathione‐mediated reduction. It is demonstrate that activated OXA promotes intratumoral accumulation of cytotoxic T lymphocytes by triggering ICD of cancer cells. Meanwhile, NLG919 downregulates IDO‐1‐mediated immunosuppression and suppresses regulatory T cells. Most importantly, PN shows much higher efficiency than free OXA or the combination of free OXA and NLG919 to regress tumor growth and prevent metastasis of mouse models of both breast and colorectal cancer.