基于“扶正祛邪”理论的高靶向仿生纳米红细胞载黄芪多糖粒子对胃癌腹腔转移灶放疗增敏的研究

Abdomen metastasis is the main factor affecting the survival rate of patients with gastric cancer.Although radiotherapy is a common way to local treatment of gastric cancer, its application is limited by the lower radiotherapy tolerance of normal tissues and organs adjacent to the abdominal lesions. How to improve the radiotherapy sensitivity of the tumor without increasing the dose of conventional irradiation is an urgent problem to be solved.Tumor hypoxia microenvironment as well as post-radiotherapy immunosuppressive microenvironment is the key to the recent and forward curative effects of tumor radiotherapy. Based on the previous research, we design a kind of biomimetic erythrocyte nanoparticles carrying oxygen and astragalus polysaccharide. The hemoglobin in the particles carrying oxygen, increasing the local oxygen of the tumor, and strengthening “vital qi”, thus enhance the “qu xie” effect of radiotherapy.As the active ingredient of astragalus well known as “bu yao zhi zhang”, astragalus polysaccharide can inhibit Tregs in tumor microenvironment after radiotherapy, and enhance immune activity, so as to strengthen “vital qi” to consolidate the “qu xie” power of radiotherapy. Both of them in the the efficient delivery nano-bionic system, target to improve the local oxygen and change the immunosuppressive microenvironment after radiotherapy. The evaluation and mechanism of the project provide a scientific basis for the subsequent development of independent intellectual property rights, and play the advantages of traditional Chinese medicine in radiotherapy sensitization system.

胃癌的腹部转移与播散是危及患者生命最主要的原因。放疗是胃癌局部治疗的常用技术，但其应用受限于腹腔病灶临近的正常组织器官较低的放疗耐受性。在不增加常规照射剂量的情况下，如何提高肿瘤的放疗敏感性，是临床迫切需要解决的难题。肿瘤乏氧的微环境以及放疗后肿瘤免疫抑制微环境是影响肿瘤放疗近期及远期效果的关键。申请人及团队在前期研究的基础上，设计一种对肿瘤靶向渗透的仿生纳米红细胞携氧载黄芪多糖粒子，粒子中血红蛋白携氧递氧，增加肿瘤局部的氧供，补气行血，“扶正”以强化放疗“祛邪”之力；以“补药之长”著称的黄芪，其有效成分黄芪多糖，抑制放疗后肿瘤微环境中Treg的负性调节，增强免疫活性，益气活血，“扶正”以巩固放疗“祛邪”之功。二者在纳米仿生体系的高效递送下，针对性地提高肿瘤局部氧供以及改变放疗后免疫抑制微环境。该项目的效果评价及机制探索为后续开发有自主知识产权的、发挥中医药优势的放疗增敏体系提供科学依据。

肿瘤乏氧的微环境以及放疗后肿瘤免疫抑制微环境是影响肿瘤放疗近期及远期效果的关键。申请人及团队在前期系列抗肿瘤纳米载药系统的研究基础之上，将制备的DSPE-PEG-iRGD嵌插于红细胞膜包载的血红蛋白-黄芪多糖共载体系上，构建了粒径均一，分散性好，包封率、载药量、稳定性达标的高靶向仿生红细胞载黄芪多糖粒子。对所制备的高靶向仿生红细胞载黄芪多糖粒子进行了系列表征和鉴定，进一步评估其肿瘤靶向穿透性、改善肿瘤局部乏氧的能力、增强胃癌腹腔转移瘤放疗效果以及生物安全性，并探索其机制。结果显示，与对照组相比，高靶向仿生红细胞载黄芪多糖粒子在胃癌腹腔转移瘤荷瘤鼠体内有明显的肿瘤靶向穿透性，有效改善肿瘤局部乏氧状态，促进免疫细胞浸润及细胞因子分泌等，从而增强放疗抗肿瘤作用。研究结果认为，高靶向仿生红细胞载黄芪多糖粒子可以安全有效地增强肿瘤放疗敏感性。