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Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery

文献类型：期刊论文

作者Xi, Ziyue1,2; Ahmad, Ejaj1; Zhang, Wei2; Li, Jingyi1; Wang, Aohua1,3; Faridoon3,4; Wang, Ning1,3; Zhu, Chunliu1; Huang, Wei3,4; Xu, Lu2
刊名JOURNAL OF CONTROLLED RELEASE
出版日期2022-02-01
卷号342页码:1-13
关键词Absorption barriers Sequential delivery Transcytosis Intracellular trafficking Insulin
ISSN号0168-3659
DOI10.1016/j.jconrel.2021.11.045
通讯作者Xu, Lu(xulu@syphu.edu.cn) ; Yu, Miaorong(mryu@simm.ac.cn) ; Gan, Yong(ygan@simm.ac.cn)
英文摘要The efficacy of oral insulin drug delivery is seriously hampered by multiple gastrointestinal barriers, especially transepithelial barriers, including apical endocytosis, lysosomal degradation, cytosolic diffusion and basolateral exocytosis. In this study, a functional nanoparticle (PG-FAPEP) with dual-modification was constructed to sequentially address these important absorption obstacles for improved oral insulin delivery. The dual surface decorations folate and charge-convertible tripeptide endowed PG-FAPEP with the ability to target the apical and basolateral sides of enterocytes, respectively. After fast diffusion across the mucus layer, PG-FAPEP could be efficiently internalized into epithelial cells via a folate receptor-mediated pathway and subsequently became positively charged in acidic lysosomes due to the surface tripeptide, triggering the proton sponge effect to escape lysosomes. When entering the cytosolic medium, PG-FAPEP was converted to neutral charge again, attenuating intracellular adhesion, and gained improved motility toward the basolateral side. Finally, the tripeptide helped PG-FAPEP recognize the proton-coupled oligopeptide transporter (PHT1) in the basolateral membrane, boosting intact exocytosis across intestinal epithelial cells. The in vivo studies further verified that PG-FAPEP could traverse the intestinal epithelium by folate receptor-mediated endocytosis, lysosomal escape, and PHT1-mediated exocytosis, exhibiting a high oral insulin bioavailability of 14.3% and a prolonged hypoglycemic effect. This formulation addresses multiple absorption barriers on demand with a simple dual-modification strategy. Therefore, these features allow PG-FAPEP to unleash the potential of oral macromolecule delivery.
WOS关键词POLYASPARTAMIDE DERIVATIVES ; PH ; ENDOCYTOSIS ; TRANSPORT
资助项目National Natural Science Foundation of China[81803445] ; National Natural Science Foundation of China[82003678] ; National Natural Science Foundation of China[82025032] ; NN-CAS foundation, Science and Technology Commission of Shanghai Municipality[20431900100] ; National Key R&D Program of China[2020YFE0201700] ; Major International Joint Research Project of Chinese Academy of Sciences[153631KYSB20190020]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000745679700001
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/300519]  
专题新药研究国家重点实验室
通讯作者Xu, Lu; Yu, Miaorong; Gan, Yong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Shenyang Pharmaceut Univ, Sch Pharm, Shenyang 110016, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Shanghai Inst Mat Med, CAS Ctr Excellence Mol Cell Sci, Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Natl Inst Food & Drug Control, NMPA Key Lab Qual Res & Evaluat Pharmaceut Excipi, Beijing 100050, Peoples R China
推荐引用方式
GB/T 7714		 Xi, Ziyue,Ahmad, Ejaj,Zhang, Wei,et al. Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery[J]. JOURNAL OF CONTROLLED RELEASE,2022,342:1-13.
APA Xi, Ziyue.,Ahmad, Ejaj.,Zhang, Wei.,Li, Jingyi.,Wang, Aohua.,...&Gan, Yong.(2022).Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery.JOURNAL OF CONTROLLED RELEASE,342,1-13.
MLA Xi, Ziyue,et al."Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery".JOURNAL OF CONTROLLED RELEASE 342(2022):1-13.

入库方式： OAI收割

来源：上海药物研究所

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