Yu Mian, Zhao Miaoqing, Yu Rilei, Chu Shaochen, Xu Jiahao, Xia Ming, Wang Cheng
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Department of Pathology, Provincial Hospital Affiliated to Shandong University, Key Laboratory for Kidney Regeneration of Shandong Province, Jinan 250021, China.
J Control Release. 2019 Jun 28;304:242-258. doi: 10.1016/j.jconrel.2019.05.007. Epub 2019 May 6.
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.
癌症免疫疗法是最令人兴奋的话题。然而，由于治疗靶点单一导致的不敏感性或免疫逃逸都会导致治疗失败。 ingenol-3-肉豆蔻酸酯（I3A）可以通过免疫疗法和化疗之间的协同作用抑制癌症，然而，由于其疏水性和pH不稳定性，其推测和准确机制在体内尚未得到证实，这也阻碍了其临床转化。在此，我们开发了一种由单醇羟基（-CH(CH3)-OH）提供“酸性核心”的聚合物胶束包裹I3A（I3A-PM），成功克服了上述问题并降低了体内毒性。为了测试协同作用，将荷S180肿瘤小鼠通过静脉内和瘤内给药给予I3A-PM，我们发现I3A-PM呈现出显著的抗肿瘤作用，并通过上调Th1细胞因子（IL-12、IL-2、IFN-γ和TNF-α）的水平促进Th1极化，加速CD4和CD8 T细胞的扩增，同时，I3A-PM通过抑制TGF-β信号通路消耗调节性T细胞、Th2细胞因子IL-6。此外，我们呼吁对肿瘤靶点进行虚拟筛选，发现I3A作为I型TGF-β受体抑制剂改善免疫刺激作用的新途径。这些结果表明I3A-PM是一种有前途的癌症免疫治疗纳米制剂。与商业产品相比，鼓励在不同癌症模型中进一步评估其协同治疗效果，以促进研究成果（I3A-PM）进入临床。
