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

Abstract

In this study, amphipathic chitosan derivatives (ACS) and cell-penetrating peptides (CPPs) co-modified colon-specific nanoparticles (CS-CPP NPs) were prepared and evaluated to improve oral bioavailability of protein and peptide drugs. ACS modification was harnessed to protect CPPs from degradation in stomach and small intestine after oral administration and achieve colon-specific drug delivery. After CS-CPP NPs arrived at colon, ACS on the surface of the NPs were gradually degraded and CPPs were exposed to bring into play the penetration efficacy in colon epithelium. Herein, we synthesized four types of ACS (TOCS, TDCS, TPCS and TSCS) and adopted three types of CPPs (Tat, Penetratin and R8) to prepare the NPs (TOCS-Tat NPs, TDCS-Tat NPs, TPCS-Tat NPs, TSCS-Tat NPs, TDCS-Pen NPs and TDCS-R8 NPs). The study of protective effects of ACS upon Tat showed that the modification of ACS exerted favourable protection upon Tat in stomach and small intestine. ACS degradation in colon were indirectly determined in viscosity method, which indicated that ACS could be gradually degraded in 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 AUC and Cmax for TDCS-Tat NPs were respectively increased by 1.45 times and 1.82 times compared with TDCS NPs. In conclusion, CS-CPP NPs as vehicles for colon-specific drug delivery system may be an efficient approach to improve oral absorption of protein and peptide drugs.

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Publication details

The article was received on 15 Nov 2018, accepted on 08 Jan 2019 and first published on 08 Jan 2019


Article type: Paper
DOI: 10.1039/C8BM01485J
Citation: Biomater. Sci., 2019, Accepted Manuscript
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    Enhanced oral absorption of insulin using colon-specific nanoparticles co-modified with amphiphilic chitosan derivatives and cell-penetrating peptides

    F. Guo, T. Ouyang, T. Peng, X. Zhang, B. Xie, X. Yang, D. Liang and H. Zhong, Biomater. Sci., 2019, Accepted Manuscript , DOI: 10.1039/C8BM01485J

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