声动力调控肿瘤微环境诱导MPCM纳米粒归巢治疗晚期三阴乳腺癌的研究

Advanced triple-negative breast cancer (TNBC) has a poor prognosis due to its metastasis and drug resistance. A treatment strategy is urgently needed to improve survival. Therefore, sonodynamic therapy has been paid more attention with excellent penetrability and has potential application prospect in advanced TNBC. In the preliminary research, the stability of macrophage cell membrane (MPCM) and ability targeting to tumor were used to synthesize nano-complex modified by MPCM carrying hemoporphyrin and adriamycin, and applied the combination of sonodynamic therapy and chemotherapy to TNBC treatment. The antitumor effect was significant at the cell level, but it was still unsatisfied in vivo. These results may be caused by low efficiency in delivering MPCM complex into TNBC (" unable to enter " ) due to microvascular occlusion in advanced TNBC , and weak effect of MPCM complex targeting TNBC (" unable to stay "). This project is to further evaluate to obtain the best time window of MPCM complex entering the tumor by opening tumor microvessels with sonodynamic power, to improve the targeting ability of MPCM complex to TNBC by constructing inflammatory environment using the inflammatory characteristics of marophages. The MPCM complex can enter, stay and highly concentrate in the tumor, achieving the purpose of effective treatment of TNBC with sonodynamic therapy combined with chemotherapy. Furthermore, a new strategy for the treatment of advanced TNBC is provided.

晚期三阴乳腺癌（TNBC）因常伴转移且易耐药，预后较差，亟需新治疗策略提高生存期。具有良好穿透性的声动力治疗因而受到重视，在晚期TNBC中有潜在应用前景。申请人前期利用巨噬细胞膜（MPCM）的稳定性和肿瘤靶向性，合成MPCM修饰的携带血卟啉和阿霉素的纳米复合体，将声动力与化疗联合应用于TNBC治疗。该方法在细胞水平抑瘤效果显著，但在体抑瘤效果仍欠佳。进一步分析，可能原因为晚期TNBC微血管闭塞致MPCM复合体输送至肿瘤内的效率低（“进不去”），及MPCM复合体靶向富集于TNBC的效果欠佳（“留不住”）。申请人拟开展进一步研究，通过微泡的血管效应开放肿瘤微血管，使MPCM复合体能进入肿瘤；通过构建肿瘤炎性环境，强化MPCM复合体对TNBC的靶向富集能力。从而使MPCM复合体“进得去”，“留得住”，高效富集于肿瘤内，实现声动力联合化疗有效治疗TNBC的目的，进而为晚期TNBC的治疗提供新策略。

晚期三阴乳腺癌（TNBC）因常伴转移且易耐药，预后较差，亟需新治疗策略提高生存期。 具有良好穿透性的声动力治疗因而受到重视，在晚期TNBC中有潜在应用前景。目前，声动力治疗早期乳腺癌已取得较好的实验研究结果。然而，由于晚期TNBC体积较大，内部微环境缺氧，因此不能提供足够的声动力治疗所需的O2。另外声敏剂在晚期肿瘤内效能不高。综上所述，O2和声敏剂作为声动力治疗所必须的两个重要因素 不能高效在肿瘤内发挥声动力治疗作用，是目前声动力治疗晚期TNBC面临的瓶颈。申请人通过将稀土元素掺杂至无机纳米声敏剂锰基材料中，利用电子重排、结构重塑等化学工艺增加材料电子空穴数量，探索声动力治疗晚期TNBC提供声敏剂改性方法，相关成果发表在【Particle & Particle Systems Characterization】。在上述基础上，申请人进一步探索锰基无机纳米声敏剂在声动力治疗晚期TNBC中的分子机理，发现该声敏剂在声动力响应下，产生的ROS通过肿瘤细胞“铁死亡”途径，将TNBC细胞膜磷脂双分子层脂质过氧化，增加细胞膜通透性，导致肿瘤细胞凋亡，相关成果发表在美国化学会旗下的生物材料杂志【ACS applied bio materials】。申请人继续通过将锰基无机纳米声敏剂改造提升性能的基础上，赋予其仿生酶特性，使其具有在声动力响应下调控晚期TNBC内微环境的生物功能，初步探索了利用生物-化学工程技术，使其提升声动力响应性的同时，具备与肿瘤内源性H2O2，发生化学反应生成O2，从而改善肿瘤内乏氧微环境，增强声动力治疗晚期TNBC的疗效，相关成果发表在【advanced science.IF:17.5】。综上所述，申请人探索了肿瘤内O2的供给，声敏剂在肿瘤内效能的提升，达到了课题的预期目标。