Metal-Organic Framework-Based Nano-Activators Facilitating Microwave Combined Therapy via a Divide-and-Conquer Tactic for Triple-Negative Breast Cancer.
Metal-Organic Framework-Based Nano-Activators Facilitating Microwave Combined Therapy via a Divide-and-Conquer Tactic for Triple-Negative Breast Cancer.
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DOI：
10.1021/acsnano.3c09734
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发表时间：
2023-12
期刊：
影响因子：
17.1
通讯作者：
Qiong Wu;Longfei Tan;Xiangling Ren;Changhui Fu;Zengzhen Chen;Jun Ren;Tengchuang Ma;Xianwei Meng
中科院分区：
文献类型：
--
作者：
Qiong Wu;Longfei Tan;Xiangling Ren;Changhui Fu;Zengzhen Chen;Jun Ren;Tengchuang Ma;Xianwei Meng
针对三阴性乳腺癌复发率和转移率高的临床问题，提出了一种分治策略。设计的纳米激活剂增强了微波热动力学化疗对原发肿瘤的杀伤作用，同时改善了免疫抑制微环境，激活了肿瘤T淋巴细胞的浸润，增强了PD-1/PD-L1免疫制剂的聚集和渗透，最终提高了免疫检查点阻断治疗的疗效，实现了对远端肿瘤和转移的有效抑制。通过将化疗药物吡罗替尼和免疫抑制剂PD-1/PD-L1抑制剂2包裹在金属有机骨架(MOF)中，然后偶联靶分子三苯基膦，合成了基于金属有机骨架(MOF)的MPPT纳米激活剂，显著促进了吡罗替尼和免疫抑制剂在肿瘤中的蓄积和渗透。除了微波辐射下微波热动力学化疗的综合治疗外，纳米激活剂中的Mn2+全面促进cGAS-STING途径激活天然免疫，微波治疗和缺氧缓解相结合改善肿瘤免疫抑制微环境。释放的吡罗替尼下调表皮生长因子受体及其下游通路PI3K/AKT/mTOR和MAPK/ERK信号通路，以最大限度地发挥免疫检查点阻断的治疗作用，有助于增强抗肿瘤效果，促进长期记忆免疫。这种纳米激活剂通过分而治之的策略为现有的临床三阴性乳腺癌治疗提供了一个普遍有希望的范例。
Aiming at the clinical problems of high recurrence and metastasis rate of triple-negative breast cancer, a divide-and-conquer tactic is developed. The designed nanoactivators enhance microwave thermo-dynamic-chemotherapy to efficiently kill primary tumors, simultaneously ameliorate the immunosuppressive microenvironment, activate the tumor infiltration of T lymphocytes, and enhance the accumulation and penetration of PD-1/PD-L1 immune agents, ultimately boosting the efficacy of immune checkpoint blocking therapy to achieve efficient inhibition of distal tumors and metastases. Metal-organic framework (MOF)-based MPPT nano-activator is synthesized by packaging chemotherapeutic drug Pyrotinib and immunosuppressant PD-1/PD-L1 inhibitor 2 into MnCa-MOF and then coupling target molecule triphenylphosphine, which significantly improved the accumulation and penetration of Pyrotinib and immunosuppressant in tumors. In addition to the combined treatment of microwave thermo-dynamic-chemotherapy under microwave irradiation, Mn2+ in the nano-activator comprehensively promotes the cGAS-STING pathway to activate innate immunity, microwave therapy, and hypoxia relief are combined to ameliorate the tumor immunosuppressive microenvironment. The released Pyrotinib down-regulates epidermal growth factor receptor and its downstream pathways PI3K/AKT/mTOR and MAPK/ERK signaling pathways to maximize the therapeutic effect of immune checkpoint blocking, which helps to enhance the antitumor efficacy and promote long-term memory immunity. This nano-activator offers a generally promising paradigm for existing clinical triple-negative breast cancer treatment through a divide-and-conquer strategy.