细胞膜仿生纳米级联反应器的构建及其在肿瘤靶向协同治疗中的应用

The tumor heterogeneity and diversity have a significant influence on the cancer therapeutic efficacy, but there is no effective strategy for cancer precision therapy. The applicant has realized cancer targeted therapy by using cell membrane-coated biomimetic drug delivery systems and synergistic therapeutic strategies. In this project, a cancer cell membrane camouflaged cascade nanoreactor would be constructed by loading glucose oxidase and pre-synthesized hydrogen peroxide responsive doxorubicin prodrug into acid sensitive metal-organic framework nanoparticles with cancer cell membrane functionalization. This cascade nanoreactor was proposed to enhance the cancer targeting efficiency by its immune escape and homotypic target abilities, transform the tumor microenvironment and accelerate cancer starvation/chemo synergistic therapeutic effects by precisely controlling drug release and activating the prodrug. Firstly, the drug loading efficiency, drug release behaviors, cascade catalytic ability and the microenvironment transformation ability of the biomimetic cascade nanoreactor would be investigated in vitro. Subsequently, the immune escape and homotypic targeting ability, and the starvation/chemo therapeutic effects of the biomimetic cascade nanoreactor would be evaluated in the homotypic cancer cells and heterotypic normal cells. Finally, a tumor mode would be established to measure the anti-cancer ability and the biocompatibility of the biomimetic cascade nanoreactor. Moreover, this project will provide new insights for the construction of intelligent drug carriers, as well as the cancer precision therapy.

肿瘤的异质性和个体化差异极大的影响肿瘤治疗效果，亟需构建肿瘤精准治疗方案。申请者前期通过细胞膜仿生纳米药物载体和协同治疗的方式实现了肿瘤靶向治疗。本项目拟采用细胞膜修饰装载有葡萄糖氧化酶和过氧化氢响应阿霉素前药的酸敏感金属有机框架纳米药物，构建具有级联催化和协同治疗性能的细胞膜仿生纳米级联反应器。本项目将通过纳米药物的高效传递、肿瘤微环境的改造、前药的精准控释及级联催化过程，形成肿瘤靶向饥饿治疗激活化学治疗的高效协同机制。首先，通过体外实验探究该仿生纳米级联反应器药物装载、级联催化、微环境改造和药物控释的性能；其次，通过细胞实验研究该细胞膜仿生纳米级联反应器免疫逃逸、同源靶向、饥饿治疗激活化疗的协同作用性能；最后，利用小鼠肿瘤模型，探究该细胞膜仿生纳米级联反应器抑制肿瘤生长的能力并评估其生物安全性。通过本项目的开展将为智能型纳米药物载体的构建和肿瘤靶向精准治疗提供新的思路。

肿瘤异质微环境和个体化差异性极大的影响治疗效果，并且抗肿瘤药物普遍面临溶解性差、靶向性差、抗肿瘤机制单一等问题。基于此，本项目设计并制备了一系列肿瘤微环境调控的靶向纳米药物，通过提高药物对肿瘤组织的靶向效率提升药物利用率，并通过调控肿瘤微环境赋予药物的抗肿瘤协同机制。利用细胞膜修饰装载有葡萄糖氧化酶和过氧化氢响应阿霉素前药的酸敏感金属有机框架纳米药物，构建了具有级联催化、肿瘤微环境调控和协同治疗性能的细胞膜仿生纳米级联反应器，实现了肿瘤靶向饥饿治疗激活化疗的协同治疗策略。为进一步提升药物对作用靶点的靶向作用效率，本项目利用多功能嵌合肽构建了针对细胞膜、细胞核、线粒体等细胞器靶向光动力嵌合肽系统，通过原位生成活性氧自由基实现精准光动力学治疗的目的。为解决传统纳米药物载体面临的装载量低、制备过程复杂，且载体的引入易诱发对机体的生物安全性隐患等问题，本项目利用药物分子自组装行为进一步构建了一系列无载体自传递纳米药物平台，可以极大的提升抗肿瘤纳米药物的载药量，并提升药物的物化性质和肿瘤靶向性质。此外，通过筛选不同功能的药物分子构建自传递纳米药物，分别实现了改善肿瘤乏氧、逆转肿瘤免疫抑制、打破肿瘤细胞抗氧化等微环境调控策略，进而实现了肿瘤靶向光动力学治疗、化疗、免疫治疗等抗肿瘤协同机制，能有效的实现原发瘤和转移瘤的协同抑制。本项目已完成预定研究目标，为肿瘤靶向策略、纳米药物的构建、肿瘤微环境调控方式及肿瘤协同治疗机制提供了新的思路和见解。在本项目资助下，本项目研究成员以通讯作者身份发表学术论文20篇，包括ACS Nano、Nano Letters、Biomaterials、journal of Controlled Release、Advanced Science等生物材料和纳米医学领域具有一定影响力的国际学术期刊，均已明确标注本基金资助，获得国家发明专利1项，培养研究生10余名，参与获得广东省科技进步奖-一等奖等奖励和荣誉。