Charge-switchable zwitterionic polycarboxybetaine particle as an intestinal permeation enhancer for efficient oral insulin delivery

Abstract

Insulin, a peptide hormone, is one of the most common and effective antidiabetic drugs. Although oral administration is considered to be the most convenient and safe choice for patients, the oral bioavailability of insulin is very low due to the poor oral absorption into blood circulation. Intestinal epithelium is a major barrier for the oral absorption of insulin. Therefore, it is vital to develop intestinal permeation enhancer to increase the antidiabetic efficacy of insulin after oral administration. Methods: Charge-switchable zwitterionic polycarboxybetaine (PCB) was used to load insulin to form PCB/insulin (PCB/INS) particles through the electrostatic interaction between positively charged PCB in pH 5.0 and negatively charged insulin in 0.01 M NaOH. The opening effect of PCB/INS particles on intestinal epithelium was evaluated by detecting the changes of claudin-4 (CLDN4) protein and transepithelial electrical resistance (TEER) after incubation or removal. The mechanism was further elucidated based on the results of Western blot and fluorescence images. The PCB/INS particles were then used for type 1 diabetes mellitus therapy after oral administration. Results: PCB could load insulin with the loading efficiency above 86% at weight ratio of 8:1. PCB/INS particles achieved sustained release of insulin at pH 7.4 due to their charge-switchable ability. Surprisingly, PCB/INS particles induced the open of the tight junctions of intestinal epithelium in endocytosis-mediated lysosomal degradation pathway, which resulted in increased intestinal permeability of insulin. Additionally, the opening effect of PCB/INS particles was reversible, and the decreased expression of CLDN4 protein and TEER values were gradually recovered after particles removal. In streptozotocin-induced type 1 diabetic rats, oral administration of PCB/INS particles with diameter sub-200 nm, especially in capsules, significantly enhanced the bioavailability of insulin and achieved longer duration of hypoglycemic effect than the subcutaneously injected insulin. Importantly, there was no endotoxin and pathological change during treatment, indicating that PCB/INS particles were safe enough for in vivo application. Conclusion: These findings indicate that this system can provide a platform for oral insulin and other protein drugs delivery.

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

“…The tips were inserted into the jejunum at the incision and beads were manoeuvred through the funnel using the blunt, sealed end of a glass capillary tube. This process was repeated using a second tip to achieve a final instilled insulin dose of 50 IU/kg [ 35 ]. The beads were pushed at least ~1 cm from the incision.…”

Zwitterionic Biomaterials

“…Analysis showed that capsid virus possesses an oppositely charged but net-neutral surface without any hydrophobic patches, demonstrating typical zwitterionic characteristics. By learning from nature, zwitterionic materials are used to enhance the mucus penetration of drug delivery vehicles, taking advantage of the nonfouling property and strong resistance to mucus tracking (Figure a). − In a representative study of zwitterionic nanocarriers for oral drug delivery, Han et al incubated PCB nanogel in reconstituted porcine stomach mucus and tracked the diffusion trajectory . It was found that PCB nanogel diffused much faster than all other nanogels made from PEG, cationic polymers, and anionic polymers.…”

Advances in oral peptide drug nanoparticles for diabetes mellitus treatment

“… [ 144 ] CPP/insulin nanocomplex core with pHPMA coating Insulin/STZ-induced T1DM rats/75 U/kg pHPMA facilitated mucus permeation. [ 77 ] Zwitterionic PCB Insulin/STZ-induced T1DM rats/50 U/kg PCB/insulin particles induced the TJs open of intestinal epithelium [ 145 ] CS-CPP modified GLP-1 loaded PLGA NPs GLP-1/Nicotinamide-STZ induced T2DM rats/300 μg/kg CS and CPP increased the intestinal permeation [ 147 ] Insulin and TMC core with pHPMA coating Insulin/STZ-induced T1DM rats/50 U/kg pHPMA facilitated mucus permeation and TMC open the TJs between epithelial cells [ 148 ] Synthetic polymer PC6 coating on CS NPs Insulin/STZ-induced T1DM rats/50 U/kg PC6 facilitated NPs across the mucus and triggered the TJs opening by covalently bind to the cysteine-rich receptors [ 149 ] Polymerized UDCA Insulin/NOD mice/285 mIU/kg pUDCA NPs functioned as a high-avidity bile-acid receptor agonist. [ 150 ] MSNs Insulin-loaded MSN modified with PLA-PEG-CPP Insulin/STZ-induced T1DM rats/80 U/kg PEG and CPP achieved hydrophilic and electroneutral interaction with mucus.…”

“…Zwitterionic PCB, with cationic quaternary ammonium group and anionic carboxyl acid group alone, is neutral at pH 7.4 and cationic in acidic environment. In our recent study, we found that charge-switchable zwitterionic PCB could load insulin through the electrostatic interaction in pH 5.0 [ 145 ]. The encapsulation efficiency of insulin was above 86%, and the diameter of PCB 122 /insulin particles was about 80 nm.…”