基于靶向纳米载体介导的声动力/NKG2A抑制剂免疫疗法协同治疗三阴性乳腺癌及机制研究

How to effectively and safely kill tumor cells while producing anti-tumor immune response, inhibit metastasis and prevent recurrence is the key to triple-negative breast cancer (TNBC) treatment. Studies have shown that sonodynamic therapy (SDT) can kill deep tumor cells, but the anti-tumor immune response is weak. Immunotherapy is expected to better activate anti-tumor immune responses as the most promising synergistic treatment model. NKG2A inhibitors activate NK cells by blocking the inhibitory receptor NKG2A, which could effectively kill tumor cells. In addition, the preliminary study of the project team has found that HMSNs have better drug-loading and targeted therapeutic properties, which can reduce the side effects of drugs in the treatment process. Based on the above, we hypothesized that basing on the targeted therapeutic agent based HMSNs carrier, and the synergistic method of SDT/NKG2A inhibitor can kill TNBC cells and enhance the body's anti-tumor immune response. We will research the biocompatibility and targeting through in vivo and in vitro experiments. We will observe the key indicators such as the growth curve of TNBC model, tumor necrosis and apoptosis, and lymphocytes to evaluate the therapeutic efficacy and illuminate the mechanism. This project will provide a new strategy in the therapy of TNBC.

如何杀灭肿瘤细胞的同时产生抗肿瘤免疫反应，抑制转移和防止复发是三阴性乳腺癌（TNBC）治疗的关键。研究证明，声动力疗法（SDT)能杀灭深层次的肿瘤细胞，但产生的抗肿瘤免疫反应较弱。免疫疗法有望更好的激活抗肿瘤免疫反应成为最有希望的协同治疗模式，NKG2A抑制剂通过阻断抑制性受体NKG2A使NK细胞激活，有效的消除肿瘤细胞。此外，项目组前期研究发现介孔二氧化硅（HMSNs）具有较好的载药及靶向治疗特性，可降低治疗过程中药物的毒副作用。据此提出假说：首先通过以HMSNs为载体构建靶向纳米治疗剂，进一步利用SDT/NKG2A抑制剂免疫疗法协同治疗TNBC，有望既能高效破坏原发肿瘤，又能增强机体抗肿瘤免疫反应。通过体外及小鼠体内实验研究靶向纳米治疗剂的生物相容性及靶向特性等。观察TNBC模型生长曲线、肿瘤坏死情况、激活的淋巴细胞情况等探索治疗效果及机制。本项目有望为TNBC治疗提供新思路。

杀灭肿瘤细胞的同时产生抗肿瘤免疫反应是抑制三阴性乳腺癌转移和防止复发的关键。因此，我们以介孔二氧化硅纳米材料为载体构建靶向纳米治疗剂，进一步利用SDT/NKG2A抑制剂免疫疗法协同治疗三阴性乳腺癌。体外和体内结果表明，以介孔二氧化硅纳米材料为载体构建的靶向纳米治疗剂HMSNs-RGD@IR780@Monalizumab可通过主、被动靶向提高药物在肿瘤处富集量。IR780作为SDT治疗中的声敏剂，在超声辐照下释放单线态氧杀伤肿瘤细胞，产生的细胞碎片刺激体内的主动抗肿瘤免疫反应，同时释放出的具有免疫原性的蛋白可供免疫细胞识别，联用NKG2A 抑制剂（Monalizumab）阻断抑制性信号通路，进而激活抗肿瘤免疫反应，增强NK细胞的活性，为三阴性乳腺癌的治疗提供了新的思路。此外，我们提出了基于ROS增强SDT抗肿瘤疗效方面的研究。设计并构建多种基于肿瘤微环境调控的新型生物材料，并建立相应的治疗体系、方法，为肿瘤治疗提供新思路。