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Mechanism Study of Cellular Uptake and Tight Junction Opening Mediated by Goblet Cell-Specific Trimethyl Chitosan Nanoparticles

2014; American Chemical Society; Volume: 11; Issue: 5 Linguagem: Inglês

10.1021/mp400685v

1543-8392

Jian Zhang, Xi Zhu, Yun Jin, Wei Shan, Yuan Huang,

Drug Transport and Resistance Mechanisms

Modifying nanoparticles with targeting peptides which can specifically bind to intestinal epithelium was recently suggested as a strategy to further enhance their ability for the oral delivery of macromolecular drugs. However, few studies were focused on comprehensive understanding of the uptake and transport processes as well as the underlying molecular signaling pathways mediated by the ligand modification. In the present study, the mechanisms of cellular uptake and the tight junction opening associated with the trimethyl chitosan based nanoparticles (M-NPs) and their goblet cell-targeting CSK (CSKSSDYQC) peptide modified nanoparticles (CSK-M-NPs) were investigated. Compared with single ion cross-linked nanoparticles (S NPs), M-NPs and CSK-M-NPs, prepared with multiple agents, exhibited superior stability which could effectively protect drugs against the degradation of trypsin. Caveolae-mediated endocytosis and macropinocytosis were involved in the intracellular uptake of both M-NPs and CSK-M-NPs on Caco-2/HT29-MTX cocultured cells. However, CSK peptide modification could further induce clathrin-mediated endocytosis of the NPs. Intriguingly, most endocytosis subpathways have been altered after CSK peptide modification. Moreover, the opening of epithelial tight junctions was investigated at both protein and gene levels. The results indicated that both M-NPs and CSK-M-NPs could transiently and reversibly open the epithelial tight junctions via the C-Jun NH2-terminal kinase-dependent pathway. However, CSK peptide modification enabled a more rapid opening and recovering of the tight junctions. In all, the enhanced uptake and transport capacity of nanoparticles after CSK peptide modification may be attributed to the alteration of internalization pathways and the stronger ability of opening tight junctions.