Enhanced oral absorption of insulin using colon-specific nanoparticles co-modified with amphiphilic chitosan derivatives and cell-penetrating peptides.

In this study, amphipathic chitosan derivative (ACS) and cell-penetrating peptide (CPP) co-modified colon-specific nanoparticles (CS-CPP NPs) were prepared and evaluated to improve the oral bioavailability of protein and peptide drugs. ACS modification was harnessed to protect CPPs from degradation in the stomach and small intestine after oral administration and achieve colon-specific drug delivery. After CS-CPP NPs reached the colon, ACSs on the surface of the NPs were gradually degraded and CPPs were exposed to bring into play the penetration efficacy in the colon epithelium. Herein, we synthesized four types of ACSs (TOCS, TDCS, TPCS and TSCS) and adopted three types of CPPs (Tat, Penetratin and R8) to prepare NPs (TOCS-Tat NPs, TDCS-Tat NPs, TPCS-Tat NPs, TSCS-Tat NPs, TDCS-Pen NPs and TDCS-R8 NPs). The study of the protective effects of ACS upon Tat showed that the modification of ACS exerted favourable protection upon Tat in the stomach and small intestine. ACS degradation in the colon was indirectly determined in the viscosity method, which indicated that ACS could be gradually degraded in the colon. Using Caco-2 cell monolayers as cell models, it was found that the cellular uptake amount and transcellular transportation performance of CS-CPP NPs were much enhanced compared with those of TDCS NPs and PVA NPs. With Bama mini-pigs as animal models, the pharmacodynamic study demonstrated that the hypoglycemic effect for insulin-loaded TDCS-Tat NPs was more significant than that for TDCS NPs, lowering the blood glucose by 40%. The pharmacokinetic study indicated that the AUC and Cmax for TDCS-Tat NPs were respectively increased by 1.45 times and 1.82 times compared with those of TDCS NPs. In conclusion, CS-CPP NPs as vehicles for colon-specific drug delivery systems may be an efficient approach to improve the oral absorption of protein and peptide drugs.