γ-PGA-Coated Mesoporous Silica Nanoparticles with Covalently Attached Prodrugs for Enhanced Cellular Uptake and Intracellular GSH-Responsive Release

Poor cellular uptake of drug delivery carriers and uncontrolled drug release remain to be the major obstacles in cancer therapy due to their low delivery efficiency. In this study, a multifunctional intracellular GSH (glutathione)-responsive silica-based drug delivery system with enhanced cellular uptake capability is developed. Uniform 50 nm colloidal mesoporous silica nanoparticles (MSNs) with mercaptopropyl-functionalized core and silanol-contained silica surface (MSNs-SHin) are designed and fabricated as a platform for drug covalent attachment and particle surface modification. Doxorubicin (DOX) with primary amine group as an anticancer model drug is covalently conjugated to the mesopores of MSNs-SHin via disulfide bonds in the presence of a heterobifunctional linker (N-Succinimidyl 3-(2-pyridyldithio) propionate). Poly(gamma-glutamic acid) (gamma-PGA) can be coated onto the particle surface by sequential electrostatic adsorption of polyethyleneimine (PEI) and.-PGA. The constructed delivery system exhibits enhanced cellular uptake via a speculated gamma-glutamyl transpeptidase (GGT)-mediated endocytosis pathway and controlled drug release capacity via intracellular GSH-responsive disulfide-bond cleavage, and thus significantly inhibits the growth of cancer cells. The multifunctional delivery system paves a new way for developing high-efficient particle-based nanotherapeutic approach for cancer treatment.