超声-肿瘤微环境双级响应的NO/O2共递送仿生纳米体系增效乳腺癌光动力治疗的研究

The insufficient accumulation of nanoparticles in tumor and the treatment tolerance induced by tumor hypoxia are the two main reasons why breast cancer treatment is poor and prone to recurrence and metastasis. In order to solve these problems, based on the “two-pronged” approach, the nanoparticles have been developed to co-deliver NO and O2 when they are triggered by ultrasound and tumor-microenvironment. The surface of nanoparticles is modified by the platelet membrane. Due to the immune escape and tumor vascular adhesion of platelet membrane proteins, the biomimetic nanoparticles achieve longer circulation time and adhere to the tumor vascular. After being triggered by ultrasound, NO is released from NO donor molecule to increase the tumor vascular permeability, resulting in high accumulation of nanoparticles at the tumor site. After that, manganese dioxide of nanoparticles catalyzes the hydrogen peroxide of the tumor microenvironment to produce O2. It can overcome tumor hypoxia to reverse treatment tolerance. Based on these two advantages of co-delivery of NO and O2, the biomimetic nanoparticles can enhance the photodynamic therapy of breast cancer and reduce metastasis. The designed nanoparticles to co-deliver dual-gas for the complex tumor microenvironment provide some novel insights for enhancing breast cancer treatment, reducing recurrence and metastasis. It may also hold a great promise for clinical application.

肿瘤部位纳米药物蓄积不足，以及肿瘤自身乏氧微环境导致的治疗耐受，是乳腺癌临床治疗效果不佳、易复发和转移的关键因素。为解决上述治疗难题，本课题基于“双管齐下”策略，依托血小板膜仿生技术，从活性气体分子入手，构建了超声和肿瘤微环境双级响应的NO/O2双气体仿生光敏纳米递送体系。针对纳米药物递送及气体定点响应释放存在的问题，我们首先利用血小板膜免疫逃逸和肿瘤血管粘附特性，延长药物血液循环时间和实现肿瘤血管靶向；其次利用超声定点激发释放NO，提高肿瘤血管通透性，增加纳米药物的蓄积；最后利用二氧化锰催化肿瘤微环境中过氧化氢释放O2，逆转肿瘤乏氧，改善治疗耐受。希望通过此双重效应增效光动力，降低肿瘤复发和转移。这种针对复杂肿瘤微环境设计的响应型双气体纳米递送体系，为提高乳腺癌治疗、降低复发和转移提供了新的设计思路，具备一定的临床应用价值。

肿瘤部位药物蓄积不足以及单一治疗效应不足等是限制肿瘤治疗，影响其复发和转移的关键因素。本项目执行期间构建了基于肿瘤微环境和近红外光等激发的气体递送纳米体系，通过释放NO促进肿瘤部位血管的渗透性，促进纳米药物的蓄积，同时利用外源刺激促进NO等的快速释放，达到高浓度治疗的效果，实现肿瘤的联合治疗。在项目执行期间，通过深入研究发现，释放的NO可以有效抑制肿瘤部位相关的血小板，抑制血小板的粘附和激活，从而降低肿瘤部位血小板释放的免疫抑制因子TGF-β的释放，减少循环肿瘤细胞（CTC）导致的肿瘤肺部转移，同时免疫细胞检测发现，肿瘤部位的效应T细胞显著增加，而Treg细胞等抑制细胞显著降低。通过利用NO对肿瘤相关血小板的抑制以及其对肿瘤血管的控制，可以高效的促进肿瘤药物的蓄积，增效肿瘤的联合治疗。同时我们在研究过程中，进一步探究利用仿生细胞膜递送体系进一步增加纳米药物的蓄积，我们利用红细胞膜的长循环特性，将红细胞膜包裹于纳米粒表面，通过细胞膜表面蛋白靶标的坚定，发现红细胞膜蛋白通过各种处理后依然保留在纳米粒的表面，通过体外巨噬细胞摄取和体内药代动力学研究发现，红细胞膜仿生纳米体系可以显著增加纳米药物的蓄积。同时考虑到红细胞膜的仿生特性，递送一氧化碳供体（CORM），并且利用肿瘤微环境中葡萄糖摄取的增加，构建了联级反应的纳米药物消耗葡萄糖，产生过氧化氢促进CO改善肿瘤治疗。本项目围绕气体在肿瘤微环境中的作用，改善纳米药物的蓄积，实现联合治疗，希望为临床肿瘤治疗提供新的方案。