我校药学院李晓辉教授团队在Nano letters上发表研究成果
发布人:wuph 发布时间:2017/7/17 16:11:47  浏览次数:50次
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基于酵母微囊介导的纳米粒靶向递送实现口服成像与治疗

周兴  张建祥  李晓辉

 

口服给药是目前应用最为广泛的给药途径。相较于静脉给药,口服给药在提高患者依从性、避免长期静脉注射后静脉炎的出现以及改善肿患者生存质量等方面具有难以比拟的优势。众所周知,靶向药物递送系统的发展已为肿瘤及慢性炎症疾病的治疗开创了新的篇章,但现有研究仍局限于静脉给药,如何在口服给药途径下实现药物的远隔靶向递送一直是人们期待解决的重大科学问题。尽管解决该科学问题具有十分重要的临床意义与迫切性,但是胃肠道复杂的酶环境及变化的pH较静脉系统对载体主动或被动靶向单元提出了更加严苛的要求,导致在口服途径下难以实现药物的靶向递送。大多口服靶向药物系统仍局限于以增加药物生物利用度为目的的消化道局部靶向(如肠道粘附系统、pH响应性结肠靶向递送系统等),构建胃肠道以外病灶的口服远隔靶向递送系统仍任重道而远,面临着巨大的挑战。

本研究团队注意到,酵母菌等、沙门氏杆菌等微生物则可经肠道集合淋巴滤泡部位的扁平细胞(M细胞)转运至肠相关淋巴组织,并通过巨噬细胞Dectin-1、CR3等受体对微生物细胞壁表面β-1,3-D-葡聚糖的识别作用吞噬并转运至机体巨噬细胞,并进一步分布于巨噬细胞较多的肿瘤、炎症与动脉粥样硬化部位。受此启发,本研究团队在导师李晓辉教授的带领下,创新性地提出通过仿生学原理模仿微生物经消化道感染途径,利用酵母微囊表面的β-1,3-D-葡聚糖构建了新型口服巨噬细胞靶向药物递送系统,并基于炎症及肿瘤部位的巨噬细胞募集作用实现炎症及肿瘤部位的口服药物靶向递送与成像。基于该假设,本文研究人员首先通过酵母菌酸碱及有机溶剂处理后可成功获得带负电荷的酵母微囊,其微囊外壁主要由β-1,3-D-葡聚糖组成,并可被巨噬细胞Dectin-1特异性识别。随后,首次发现酵母微囊可基于与正电荷纳米粒之间的静电作用成功构建正电荷纳米粒/酵母微囊系统,并进一步对该系统在炎症及肿瘤靶向成像中的应用进行评价,结果发现酵母微囊口服给药后可靶向分布于单核/巨噬细胞,并基于炎症及肿瘤部位的巨噬细胞募集作用实现炎症及肿瘤部位的靶向,提高炎症及肿瘤部位的成像效果,并对其靶向转运机制进行了深入系统的研究。

上述研究结果于2017年1月发表于Nano letters(IF=13.798)。该口服靶向药物递送系统的构建有望为巨噬细胞相关疾病的口服靶向治疗提供新的设计思路,因其较高的安全性及有效性有望应用于临床,为患者提供一条高效安全的口服靶向治疗策略。论文的主要完成单位为第三军医大学药学系药剂学教研室,主要通讯作者为李晓辉、张建祥教授,主要第一作者为周兴讲师。

  

Yeast Microcapsule-Mediated Targeted Delivery of Diverse Nanoparticles for Imaging and Therapy via the Oral Route

Xing Zhou,*†,‡Xiangjun Zhang,*†,§Songling Han,*,Yin Dou,†,‡Mengyu Liu,†,‡Lin Zhang,JiaweiGuo, Qing Shi,Genghao Gong,Ruibing Wang,§Jiang Hu,#,Xiaohui Li,#,‡and Jianxiang Zhang, #,†,‡

Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China

Institute of MateriaMedica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China

§State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa,8 Macau, China

Department of Radiation, Southwest Hospital, Third Military Medical University, Chongqing 400038, China

Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States

Abstract

Targeting of nanoparticles to distant diseased sites after oral delivery remains highly challenging due to the existence of many biological barriers in the gastrointestinal tract. Here we report targeted oral delivery of diverse nanoparticles in multiple disease models, via a “Trojan horse” strategy based on a bioinspired yeast capsule (YC). Diverse charged nanoprobes including quantum dots (QDs), iron oxide nanoparticles (IONPs), and assembled organic fluorescent nanoparticles can be effectively loaded into YC through electrostatic force-driven spontaneous deposition, resulting in different diagnostic YC assemblies. Also, different positive nanotherapies containing an anti-inflammatory drug indomethacin (IND) or an antitumor drug paclitaxel (PTX) are efficiently packaged into YC. YCs containing either nanoprobes or nanotherapies may be rapidly endocytosed by macrophages and maintained in cells for a relatively long period of time. Post oral administration, nanoparticles packaged in YC are first transcytosed by M cells and sequentially endocytosed by macrophages, then transported to neighboring lymphoid tissues, and finally delivered to remote diseased sites of inflammation or tumor in mice or rats, all through the natural route of macrophage activation, recruitment, and deployment. For the examined acute inflammation model, the targeting efficiency of YC-delivered QDs or IONPs is even higher than that of control nanoprobes administered at the same dose via intravenous injection. Assembled IND or PTX nanotherapies orally delivered via YCs exhibit remarkably potentiated efficacies as compared to nanotherapies alone in animal models of inflammation and tumor, which is consistent with the targeting effect and enhanced accumulation of drug molecules at diseased sites. Consequently, through the intricate transportation route, nanoprobes or nanotherapies enveloped in YC can be preferentially delivered to desired targets, affording remarkably improved efficacies for the treatment of multiple diseases associated with inflammation.

 

Keywords: drug delivery; imaging; microcapsule; nanoparticle; oral targeting; Yeast

全文链接:http://dx.doi.org/10.1021/acs.nanolett.6b04523

 

李晓辉,第三军医大学药学系药剂学教研室及重庆市药效评价中心主任,科学中国人2015年度人物,重庆市首批百名学术学科领军人才,国家新药评审专家,中国医药教育协会副会长,中国抗炎免疫药理专委会主任委员。主持完成新建药剂教研室、重庆市药效评价中心及生物医药国际产学研联盟(重庆)建设,形成了新药创制体系;承担国家重点国际合作、军特药重大专项、863等国家、军队重大重点课题40项,主持研发系列创新新药,已获国家新药证书及生产批文各1项,获国际/国家发明专利授权12项,产生了显著社会军事效益;获国家科技进步二等奖1项,省部级科技进步一等奖2项,军队科技进步二等奖2项、三等奖3项;主编、副主编著作、教材10部,参编30余部;在Cell系列Immunity、ProgPolymSci等国内外重要期刊发表论文300余篇;带领团队并与全校同仁一道,成功实现了我校“药理学与毒理学学科”进入国际ESI排名前1%的历史性突破,3次荣立个人三等功、1次集体三等功。

周兴,第三军医大学药学系药剂学教研室,讲师,博士。研究方向立足于纳米医学、仿生医学等新型药物递送系统的研究,主要关注口服给药中的热点与难点问题,在药物的口服缓、控释及口服胃肠道外病灶的远隔靶向递送方面进行了系列的研究。已在Nano  letters、ACS Nano、Biomaterials、Acta biomaterial、Polymer chemistry、Soft matter 、International journal of pharmaceutics等发表论文10余篇(第一作者发表5篇,影响累计因子35分)。承担科研课题4项,主持国家自然科学基金青年项目1项。


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