Zwitterionic micelles efficiently deliver oral insulin without opening tight junctions

Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading t...

Full description

Saved in:
Bibliographic Details
Published inNature nanotechnology Vol. 15; no. 7; pp. 605 - 614
Main Authors Han, Xiangfei, Lu, Yang, Xie, Jinbing, Zhang, Ershuai, Zhu, Hui, Du, Hong, Wang, Ke, Song, Boyi, Yang, Chengbiao, Shi, Yuanjie, Cao, Zhiqiang
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.07.2020
Subjects
3T3 Cells
Absorption
Administration, Oral
Animals
Betaine
Bioavailability
Biocompatibility
Caco-2 Cells
Drug delivery
Drug Delivery Systems
Epithelial cells
Epithelium - ultrastructure
Humans
Insulin
Insulin - administration & dosage
Intestine
Ions
Male
Mice
Mice, Inbred C57BL
Micelles
Mucus
Mucus - chemistry
Nanoparticles - chemistry
Penetration
Phosphatidylethanolamines - chemistry
Protein transport
Proteins
Rats
Safety
Swine
Tight junctions
Tight Junctions - metabolism
Viruses
Zwitterions
Online AccessGet full text

Cover

More Information
Summary:Oral delivery of protein drugs is considered a life-changing solution for patients who require regular needle injections. However, clinical translation of oral protein formulations has been hampered by inefficient penetration of drugs through the intestinal mucus and epithelial cell layer, leading to low absorption and bioavailability, and safety concerns owing to tight junction openings. Here we report a zwitterionic micelle platform featuring a virus-mimetic zwitterionic surface, a betaine side chain and an ultralow critical micelle concentration, enabling drug penetration through the mucus and efficient transporter-mediated epithelial absorption without the need for tight junction opening. This micelle platform was used to fabricate a prototype oral insulin formulation by encapsulating a freeze-dried powder of zwitterionic micelle insulin into an enteric-coated capsule. The biocompatible oral insulin formulation shows a high oral bioavailability of >40%, offers the possibility to fine tune insulin acting profiles and provides long-term safety, enabling the oral delivery of protein drugs.
Bibliography:X.H., Y.L., J.X. and E.Z. contributed equally to this work. Z.C., X.H., Y.L. and J.X. conceived and designed the experiments. X.H. conducted all the experiments except the nanogel transport and cell toxicity experiments. J.X. conducted the nanogel transport experiment. Y.L. contributed mouse experiment. E.Z performed the cell toxicity and live/dead experiment and histological staining. B.S. helped with the synthesis of DSPE-PCB and formulation. K.W. and Y.S. helped with the transmission electron spectroscopy imaging. E.Z. H.D. and H.Z. helped with the animal experiments. C.Y contributed the cell uptake flow cytometry experiment. All authors discussed the results and commented on the manuscript. Z.C., X.H. and Y.L. outlined and wrote the paper. Z.C. developed the concept and supervised the study.
Author Contributions
ISSN:1748-3387
1748-3395
DOI:10.1038/s41565-020-0693-6