Thiolated polymer and Cell-Penetrating Peptide dual-surface functionalization of mesoporous silicon nanoparticles to overcome intestinal barriers

For orally administered nanocarriers, being efficiently absorbed by the epithelium and penetrating through the mucus that covers the epithelium are twin challengeable barriers on the way to make drugs work. However, mucus penetration and epithelial absorption require quite different surface properties that nanocarriers possess. Thereby, we designed a dual-surficial-functionalized mesoporous silica nanoparticles (MSN) with thiolation Polymer (PSH) and Cell-Penetrating Peptide (CPP), which promote the mucoadhesion and cellular interactions, respectively, to boost the intestinal permeability of MSN-CPP-PSH, for efficient delivery of oral drugs. As a result, MSN-CPP-PSH showed excellent penetration across the mucus layer and high epithelial absorption using a mucus-secreting epithelial cell model. After investigating the behavior and integrity of MSN-CPP-PSH in the process of mucus penetrating and epithelium uptaking, the PSH molecules were observed gradually dissociated from the surface of MSN as it penetrated across mucus, and the CPP-covering core was revealed in time for the subsequent transepithelial transport. Biodistribution studies demonstrated this newly thiolated-polymers had quite mucoadhesive strength and greatly increased the intestinal residence time. Finally, MSN-CPP-PSH exhibits 6.76-fold in the relative bioavailability of lopinavir (LNV), as compared to oral free LNV. Our study demonstrated this newly synthesized PSH can play as a dissociable “mucus-adherent” agent to facilitate mucoadhesion and mucopenetration of nanocarriers, and also provided a strategy to overcome the diffusion barrier of mucus and absorption barrier of epithelium simultaneously.