基于表面涂层益生菌的肿瘤抗原口服递送系统  

Coated probiotic-based drug carriers for oral delivery of tumor antigens

作　　者：林思思 潘超 张一帆 刘尽尧 LIN Sisi;PAN Chao;ZHANG Yifan;LIU Jinyao(Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai Cancer Institute,Shanghai 200011,China;Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Institute of Molecular Medicine,Shanghai 200127,China)

机构地区：[1]上海交通大学医学院附属仁济医院,上海市肿瘤研究所,上海200011 [2]上海交通大学医学院附属仁济医院,分子医学研究院,上海200127

出　　处：《合成生物学》2022年第4期810-820,共11页Synthetic Biology Journal

基　　金：国家自然科学基金(21875135)。

摘　　要：肿瘤疫苗是一种通过递送肿瘤抗原进而激活自身特异性抗肿瘤免疫的肿瘤免疫疗法。口服具有方便、简单和高效的优势。然而现有的口服肿瘤疫苗有限,并且局限于胃肠道肿瘤的治疗。这主要与缺乏先进的口服递送载体有关。本研究设计了一种酵母细胞膜包覆的益生菌应用于口服递送系统。其中,酵母细胞膜发挥益生菌和抗原保护以及肠道淋巴系统靶向的作用;益生菌发挥搭载抗原和免疫佐剂的作用。结果显示,与裸菌相比,酵母细胞膜包覆能提高益生菌的生物利用度,增强其在派氏结的富集,促进树突状细胞的活化和抗原递呈以及小鼠血浆中OVA-IgG水平。实验证明该系统能够保护益生菌和抗原免受胃肠道环境刺激并进一步向肠道淋巴系统递送抗原,激活抗肿瘤免疫。Cancer vaccines, as a form of cancer immunotherapy, trigger host anti-tumor immunity by delivering tumor antigens. Oral administration has the advantages of convenience, simplicity and high efficacy. However, oral tumor vaccines have been rarely reported and existing forms are solely suitable for gastrointestinal cancer. The situation is associated with lack of advanced oral delivery systems. In this study, yeast cell membrane-coated probiotics are developed as drug carriers for oral delivery of tumor antigens. Yeast cell membranes play a dual role in protecting probiotics and antigens and facilitating targeted delivery of tumor antigens to the gut lymphatic system, while probiotics serve as both immune adjuvant and antigen carrier. As a model antigen, ovalbumin(OVA) is loaded onto probiotic surface by complexing with polyethyleneimine and hyaluronic acid via electrostatic interaction. Subsequently,antigen-loaded probiotics are individually camouflaged with yeast membranes by physical extrusion through a porous membrane. As reflected by similar growth to uncoated probiotics, both the coating and preparation procedures have limited influences on bacterial viability. Experimental results show that, compared to unmodified bacteria, yeast cell membrane coated probiotics retain their ability to grow and divide after incubation in simulated gastrointestinal environments and exhibit an improved bioavailability following oral ingestion. The presence of embedded β-glucan on yeast membranes promotes the phagocytosis by microfold cells that locate in intestinal epithelium. After oral gavage,the coating facilitates the accumulation of wrapped probiotics in Peyer’s patches and then in mesenteric lymph nodes.Furthermore, the maturation of dendritic cells and corresponding antigen presentation are enhanced by coated probiotics, which induce an OVA-specific immune response as manifested by an upgraded serum level of OVA-IgG in mice after oral administration. These results demonstrate that yeast cell membrane-coated probiotics

关 键 词：益生菌 肿瘤疫苗 口服疫苗 口服递送系统 生物纳米技术 

分 类 号：R392[医药卫生—免疫学]