Construction Of Mesoporous Silica Nanocarrier For Overcoming Multiple Gastrointestinal Barriers And Real-time Imaging

For poorly soluble drugs,dissolution process determines the rate and degree of drug absorption.Consequently,the purpose of this study to develop mesoporous silica nanoparticles(MSNs)loaded with insoluble drug which can enhance the dissolution rate and improve the oral bioavailability.However,oral administration of nanocarriers remains a significant challenge in the pharmaceutical science.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.The surface chemistry and size of nanoparticles can greatly impact their interaction with biological pathways and alter efficacy.However,the interplay between surface modification and particle size has not been well investigated especially for oral delivery.It is necessary to maximize the bioavailability of loading therapeutics.Here,we prepared different sized mesoporous silica nanoparticles(100-500 nm)and conjugated them with polyethylenimine-coated carbon dots(PCD)for effective transepithelial absorption.The nanoparticles were also coated with polyethylene glycol(PEG)polymers for improved mucus permeability.These mesoporous silica nanoparticles conj ugated to PCD and coated in PEG(MSN@PCD@PEG)were used to study the influence of particle size and surface chemistry on transepithelial transport and bioavailability.Results demonstrated that the MSN@PCD@PEG with a diameter 250 nm had the highest transepithelial transport and oral bioavailability compared to other formulations.Drug release,endocytosis pathways,transepithelial transport and degradation of these different nanocarriers were systematically studied in order to investigate effects of size variety.The findings indicated that nanoparticle-based oral drug delivery can be potentially improved by adjusting physicochemical properties.As mentioned above,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 were 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 dualmodified 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.