posted on 2023-01-03, 17:48authored byHuapan Fang, Linfu Chen, Zheng Deng, Yunxuan Gao, Yang Yang, Qian Chen, Zhuang Liu
Oral
administration of protein drugs has always been challenging
owing to various intestinal barriers. Herein, we developed an efficient
oral protein delivery strategy by using in situ polymerization
of zwitterions to encapsulate proteins, which were then loaded into
enteric coated capsules for oral feeding. After oral administration
of such capsules, the enteric coating would be degraded once the capsule
enters the intestine, releasing polyzwitterion/protein nanocomplexes.
With the help of polyzwitterion modification, such nanocomplexes were
able to pass through the mucus and cellular barriers, likely by the
proton-assisted amino acid transporter 1 (PAT1) pathway. Such a polyzwitterion-based
protein encapsulation strategy could allow for effective oral delivery
of different proteins, including bovine serum albumin (BSA), insulin,
and antibodies. Using this strategy, the oral bioavailabilities of
insulin and immunoglobin G (IgG) were measured to be as high as 16.9%
and 12.5%, respectively. Notably, oral feeding of polyzwitterion/insulin
capsules could effectively lower the blood glucose level of diabetic
animals (mice, rats, and pigs). Moreover, polyzwitterion/antiprogramed
death-1 (αPD-1) capsules were able to induce efficient antitumor
immune responses, showing significant tumor inhibition effects toward
B16F10- and 4T1-tumor bearing mouse models after oral administration.
No significant toxic effect was observed for such oral protein formulations
in the treated animals. Our work presents a strategy for the efficient
oral delivery of protein drugs, including those with large molecular
weights (e.g., antibodies) that
can hardly be orally delivered using existing technologies.