Huapan 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.
In recent years, zwitterionic materials have drawn great attention in oral drug delivery system due to their capacity for rapid mucus diffusion and enhanced cellular internalization. However, zwitterionic materials tend to show strong polarity that was hard to directly coat hydrophobic nanoparticles (NPs). Inspired by Pluronic coating, a simple and convenient strategy to coat NPs with zwitterionic materials using zwitterionic Pluronic analogs was developed in this investigation. Poly(carboxybetaine)-poly(propylene oxide)-Poly(carboxybetaine) (PCB-PPO-PCB, PPP), containing PPO segments with MW > 2.0 kDa, can effectively adsorb on the surface of PLGA NPs with typical core-shell spherical in shape. The [email protected] NPs were stable in gastrointestinal physiological environment and sequentially conquered mucus and epithelium barriers. Proton-assisted amine acid transporter 1 (PAT1) was verified to contribute to the enhanced internalization of [email protected] NPs, and the NPs could partially evade lysosomal degradation pathway and utilize retrograde pathway for intracellular transport. In addition, the enhanced villi absorption in situ and oral liver distribution in vivo were also observed compared to [email protected] NPs. Moreover, insulin-loaded [email protected] NPs as an oral delivery application for diabetes induce a fine hypoglycemic response in diabetic rats after oral administration. The results of this study demonstrated that zwitterionic Pluronic analogs-coated NPs might provide a new perspective for zwitterionic materials application as well as oral delivery of biotherapeutics.
危险品化学品经营许可证（带存储）