仿生型声/光响应载氧载药复合物改善免疫抑制微环境及增强肿瘤化疗免疫治疗的研究

抗癌药阿霉素在杀伤肿瘤细胞的同时能够诱导免疫原性细胞死亡而激发机体抗肿瘤免疫反应，但传统化疗的免疫应答较弱，目前缺乏有效的化疗免疫综合治疗平台。我们前期制备了声/光双响应载阿霉素脂质体-微泡复合物并证实超声靶向微泡破坏技术（UTMD）及光热治疗可以提高阿霉素递送效率和肿瘤杀伤效果。此外UTMD及光热治疗还通过增加肿瘤特异性淋巴细胞募集而增强抗肿瘤免疫治疗，但是肿瘤乏氧诱导的免疫抑制微环境严重影响了化疗免疫治疗效果。为提高药物递送效率，改善免疫抑制微环境并增强抗肿瘤化疗免疫，我们拟用巨噬细胞膜包裹阿霉素脂质体，再与载IR780携氧微泡连接，制备可视化仿生型声/光响应载氧载药脂质体-微泡复合物。建立小鼠4T1乳腺癌模型，探究复合物肿瘤靶向成像及生物分布。通过检测肿瘤氧合情况及体内外免疫应答效应，探讨复合物氧气递送同时联合UTMD及光热治疗对免疫抑制微环境及阿霉素抗肿瘤免疫应答的影响及其机制。

Doxorubicin, one of chemotherapeutics, is not only able to kill cancer cells but also able to induce immunogenic cell death (ICD) in the host and reactivate the anti-tumor immune response. However, weak immune response after chemotherapy is usually observed. As a result, an integrated theranostic platform for boosting chemo-immuno combination therapy is in need. An acoustic/photo-responsive doxorubicin loaded hybrid system has been prepared before, and confirmed that improved doxorubicin delivery efficiency and tumor killing effect could be achieved in combination with ultrasound microbubble targeted destruction technology (UTMD) and photothermal therapy. The enhanced anti-tumor immunotherapy by increasing the recruitment of tumor-infiltrating lymphocytes attribute to UTMD and photothermal therapy has been proved by a series of studies. In addition, immunosuppressive microenvironment induced by tumor hypoxia is an important factor in the failure of immunotherapy. In order to improve doxorubicin delivery efficiency, modulate the immunosuppressive tumor microenvironment and enhance chemo-immunotherapy, we intend to connect macrophage membrane encapsulated doxorubicin loaded liposome with IR780 and oxygen loaded microbubble to prepare visual biomimetic acoustic/photo-responsive oxygen and drug loaded hybrid system. Experiment is carried out in 4T1 breast cancer bearing mice. The ultrasound/NIR fluorescence imaging and the biodistribution of hybrid system are tested. The effect and mechanism of oxygen delivery and hybrid system combined with UTMD and photothermal therapy to immunosuppressive microenvironment and anti-tumor chemo-immunotherapy are explored by detecting tumor oxygenation and activation of immune response both in vivo and in vitro.