Transferrin Functionization Elevates Transcytosis of Nanogranules across Epithelium by Triggering Polarity-Associated Transport Flow and Positive Cellular Feedback Loop.
ACS nano(2019)
摘要
Overcoming the epithelial barriers to enhance drug transport is a focused topic for gastrointestinal, intratracheal, intranasal, vaginal and intrauterine delivery. Nanomedicines with targeting functionization promote such a process owing to specific ligand-receptor interaction. However, compared to the cell uptake of targeting nano-therapies, currently few studies concentrate on their transcytosis including endocytosis for 'in' and exocytosis for 'out'. In fact, the cellular regulatory mechanism for these pathways, as well as the principle of ligand's effect on the transcytosis, are almost ignorant. Here, we fabricated transferrin (Tf) functionalized nanogranules (Tf-NG) as the nanomedicine model, and confirmed the difference in polar distributions of Tf receptors (TfR) between two epithelium models (bipolarity for Caco-2 and unipolarity for MDCK cells). Compared to the non-specific reference, Tf-conjugation boosted the endocytosis by different pathways in two cell models, and transformed the intracellular route of Tf-NG in both cells differently, affecting exocytosis, recycling, degradation but not secretion pathway. Only bipolar cells could establish a complete transport flow from 'in' to 'out', leading to the enhanced transcytosis of Tf-NG. Importantly, epithelia could make responses to Tf-NG transcytosis. Based on the quantitative proteomics, the intracellular trafficking of Tf-NG altered the protein expression profiles, in which the endocytosis- and transcytosis-related proteins were specifically upregulated. Particularly, only bipolar cells could positively feed back to such trafficking via accelerating the subsequent Tf-NG transcytosis. Here, all the cell transport of Tf-NG was polarity-associated. In summary, Tf-modification elevated the transcytosis of Tf-NG across epithelium by triggering polarity-associated transport flow and positive cell feedback loop. These findings provided an insight to the targeting nano-delivery for efficient transport through epithelial barriers.
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关键词
transcytosis,transferrin functionalized nanogranules,polarity,cell response,proteomics,nano systematic biology
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