Nanotechnology-mediated immunochemotherapy with Ingenol-3-Mebutate for Systematic Anti-tumor Effects
Nanotechnology-mediated immunochemotherapy with Ingenol-3-Mebutate for Systematic Anti-tumor Effects
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纳米技术介导的 Ingenol-3-Mebutate 免疫化疗具有系统抗肿瘤作用
DOI：
10.1016/j.jconrel.2019.05.007
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发表时间：
2019-06-28
影响因子：
10.8
通讯作者：
Wang，Cheng
中科院分区：
文献类型：
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作者：
Yu，Mian;Zhao，Miaoqing;Wang，Cheng
癌症免疫治疗是最令人兴奋的话题。然而，由于治疗靶点单一或免疫逃避导致的不敏感性导致治疗失败。Ingenol-3-mebutate（I3 A）通过免疫和化疗的协同作用发挥抗肿瘤作用，但由于I3 A的疏水性和pH不稳定性，其作用机制尚未在体内得到证实，也阻碍了其临床应用。本文中，我们开发了一种具有由单醇羟基（-CH（CH 3）-OH）提供的“酸性核心”的聚合物胶束，其成功地克服了上述问题并降低了体内毒性。为了验证I3 A-PM的协同作用，我们将I3 A-PM通过静脉注射和瘤内注射给S180荷瘤小鼠，发现I3 A-PM具有显著的抗肿瘤作用，并通过上调Th 1细胞因子水平而促进Th 1极化（IL-12、IL-2、IFN-γ和TNF-α），并加速CD 4+和CD 8 +T细胞的扩增，同时I3 A-PM耗竭调节性T细胞，Th 2细胞因子IL-6通过抑制TGF-β信号通路。此外，我们呼吁肿瘤靶点的虚拟筛选，并发现I3 A作为TGF-β I型受体抑制剂提高免疫刺激效应的新途径。这些结果表明I3 A-PM是一种有前途的癌症免疫治疗策略的纳米药物。与商业产品相比，鼓励在不同的癌症模型中进一步评估协同治疗作用，以促进研究发现（I3 A-PM）进入临床。
Cancer-Immunotherapy was the most exciting topic. However, either insensitivity due to singleness of therapeutic target or immune evasion leads to the failure of the treatment. Ingenol-3-mebutate (I3A) can inhibit cancer through synergy between immunotherapy and chemotherapy, however, the speculation and accurate mechanism haven't been confirmed in vivo limited by its hydrophobicity and pH-instability, which also hindered its clinical translation. Herein we developed a polymeric micelle with ‘acidic core’ provided by single alcoholic hydroxyl (-CH(CH3)-OH) encapsulating I3A (I3A-PM), which successfully overcome the aforementioned problems and reduce the toxicity in vivo. To test the synergy, S180 tumor-bearing mice were subjected to I3A-PM through intravenous and intratumoral administration, we found I3A-PM presented significant antitumor effect, and promoted Th1 polarization by upregulating the level of Th1 cytokines (IL-12, IL-2, IFN-γ and TNF-α), and accelerated the expansion of CD4+and CD8+T cells, meanwhile, I3A-PM depleted regulatory T cells, Th2 cytokine IL-6 through inhibiting TGF-β signaling pathway. Furthermore, we appealed to virtual screening of tumor target, and found a new pathway of I3A as a TGF-β receptor type I inhibitor to improve immunostimulatory effects. These results demonstrated I3A-PM as a promising nanoagent for cancer immunotherapy strategy. The synergistic therapeutic effects are encouraged to further evaluate in different cancer model compared with commercial products to facilitate research finding (I3A-PM) entering the clinic.