Overcoming multiple gastrointestinal barriers by bilayer modified hollow mesoporous silica nanocarriers.

Unlabelled: Oral administration of nanocarriers remains a significant challenge in the pharmaceutical sciences. The nanocarriers must efficiently overcome multiple gastrointestinal barriers including the harsh gastrointestinal environment, the mucosal layer, and the epithelium. Neutral hydrophilic surfaces are reportedly necessary for mucus permeation, but hydrophobic and cationic surfaces are important for efficient epithelial absorption. To accommodate these conflicting surface property requirements, we developed a strategy to modify nanocarrier surfaces with cationic cell-penetrating peptides (CPP) concealed by a hydrophilic succinylated casein (SCN) layer. SCN is a mucus-inert natural material specifically degraded in the intestine, thus protecting nanocarriers from the harsh gastric environment, facilitating their mucus permeation, and inducing exposure of CPPs after degradation for further effective transepithelial transport. Quantum dots doped hollow silica nanoparticles (HSQN) with a diameter around 180 nm was used as the nanocarrier and demonstrated as high as 50% loading efficacy of paclitaxel, a model drug with poor solubility and permeability. The dual layer modification strategy prevented premature drug leakage in stomach and maintained high mucus permeation (the trajectory spanned 9-fold larger area than single CPP modification). After intestinal degradation of SCN by trypsin, these nanocarriers exhibited strong interaction with epithelial membranes and a 5-fold increase in cellular uptake. Significant transepithelial transport and intestinal distribution were also observed for this dual-modified formulation. A pharmacokinetics study on the paclitaxel-loaded nanocarrier found 40% absolute bioavailability and 7.8-fold higher AUC compared to oral Taxol®. Compared with single CPP modified nanocarriers, our formulation showed increased in vivo efficacy and tumor accumulation of the model drug with negligible intestinal toxicity. In summary, sequential modification with CPP and SCN layers on HSQN offers a potential strategy to overcome the multiple barriers of the gastrointestinal tract.

Statement Of Significance: Oral administration of nanocarriers remains a big challenge due to the multiple gastrointestinal barriers. In order to achieve both strong mucus permeation and efficient epithelial absorption, we modified the surface of silica nanoparticles with two layers: cell penetrating peptide (CPP) layer and succinylated casein (SCN) layer. The newly developed nanoformulations are demonstrated to have the following advantages: 1) versatile carrier with easy preparation, 2) high drug loading especially for poor soluble molecules, 3) reduced drug leakage in the stomach, 4) effective mucus penetration and transepithelial transport and 5) good biocompatibility, which in all indicate a great potential of this bilayer-modification strategy to facilitate the oral delivery of therapeutic agents.