主动渗透型酵母囊泡仿生纳米药物抗肿瘤活性研究  

Anti-tumor activity of yeast vesicle biomimetic nanomedicine with the ability of active tumor penetration

作　　者：刘军杰 许丽华 张开翔 赵秀 王翼扬 史进进[1] 张振中[1] LIU Jun-jie;XU Li-hua;ZHANG Kai-xiang;ZHAO Xiu;WANG Yi-yang;SHI Jin-jin;ZHANG Zhen-zhong(School of Pharmaceutical Sciences,Zhengzhou University,Zhengzhou 450001,China)

机构地区：[1]郑州大学药学院,河南郑州450001

出　　处：《药学学报》2022年第1期222-232,I000,I0007,共13页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(31900991,82073787,82172762,81874304,82073395)。

摘　　要：肿瘤致密的细胞外基质(extracellular matrix,ECM)严重限制了纳米药物的深部渗透,削弱了其抗肿瘤效果。基于此,本研究构建了具有肿瘤组织主动深部渗透能力的酵母囊泡仿生纳米药物,以期提高抗肿瘤效果。体外表征结果显示,分离的酵母囊泡(yeast cell vesicles,YCV)为规则球形,分散性良好,粒径约100 nm。以抗肿瘤药物多柔比星(doxorubicin,DOX)为模型药物,构建YCV/DOX纳米药物,DOX的包封率为82.5%,且DOX的释放具有显著的pH依赖性;细胞实验结果显示,相比于脂质体,YCV在3D肿瘤球中表现出更强的渗透能力,推测其机制可能为YCV具有良好的形变能力。4T1荷瘤小鼠(动物实验符合中国实验动物护理和使用准则,并经郑州大学实验动物伦理委员会批准)体内药效实验结果表明,YCV/DOX具有更强的肿瘤组织渗透能力,且有效抑制肿瘤生长。本研究为克服实体瘤的组织屏障和发展新型仿生纳米药物带来新思路。The dense extracellular matrix(ECM)of the tumor severely limits the deep penetration of nano‐medicine and weakens its anti-tumor effect.Based on this,the yeast vesicle biomimetic nanomedicine with active deep penetration ability of tumor tissue was designed and developed for enhanced tumor therapy.Results of charac‐terization showed that the yeast cell vesicles(YCV)displayed a spherical morphology with diameter of around 100 nm and was well dispersed.Then the chemotherapeutic drug doxorubicin(DOX)was selected as a model drug,and DOX was loaded into YCV to obtain YCV/DOX through electrostatic interaction,the encapsulation efficiencies of DOX were calculated as 82.5%.The drug release profile of YCV/DOX implied that DOX release showed a manner of pH-dependent,it may be that pH has affected the electrostatic effect of YCV and DOX.Compared with lipo‐somes(Lipo),in vitro cell experiments showed that YCV from natural sources had stronger permeability in threedimensional multicellular spheres.It is speculated that the mechanism may be good deformation capacity of YCV.A 4T1 xenograft tumor model was established to evaluate the therapeutic efficacy of YCV/DOX.The results suggested that YCV/DOX has stronger tumor tissue penetration ability and could effectively inhibit the tumor growth.All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of Zhengzhou University.This study brings new ideas for the development of biomimetic nanomedicine to overcome the ECM of solid tumors.

关 键 词：细胞外基质 细胞衍生的颗粒 纳米药物 PH敏感 抗肿瘤活性 

分 类 号：R943[医药卫生—药剂学]