Transport Mechanisms of Butyrate Modified Nanoparticles: Insight into "Easy Entry, Hard Transcytosis" of Active Targeting System in Oral Administration.

The intestinal epithelium constitutes a major barrier for orally delivered nanoparticles (NPs). Although surface ligand modification can increase cellular uptake of NPs, the transepithelial transport of active targeting NPs is relatively limited. The phenomenon is described as "easy entry, hard transcytosis". However, underlying mechanisms and potential solutions of this phenomenon are unclear. Here, butyrate modified polyethylene glycol coated NPs (Bu-PEG NPs) were chosen as the model active targeting NPs. Transport mechanism studies were performed to get a better understanding of intracellular trafficking and exocytosis fate. Results showed that after active binding to monocarboxylate transporter-1 (MCT-1), Bu-PEG NPs went through endolysosomal pathways, endoplasmic reticulum/Golgi recycling routes, and microtubule-dependent shuttling within Caco-2 cells. Then a larger proportion of Bu-PEG NPs was exocytosed from apical side. Notably, increasing the basal expression of MCT-1 by leptin facilitated basal exocytosis and transcytosis of Bu-PEG NPs, which confirmed that enhanced receptor recognition could promote "basal exit". In addition to the effect of receptor recognition, surface properties also influenced the bidirectional exocytosis of Bu-PEG NPs. When surface hydrophobicity increased, Bu-PEG NPs were dominantly exocytosed from basal membrane. Hence, two strategies may help to overcome "hard transcytosis" of active targeting NPs. One is to enhance their affinity with basal membrane by reinforcing the receptor-ligand interaction; the other is to weaken apical exocytosis by optimizing surface hydrophobicity. Thereby, this study might provide important implications for the rational design of NPs to further increase transepithelial transport efficiency.