Gene-Directed Enzyme Prodrug Therapy by Dendrimer-Like Mesoporous Silica Nanoparticles against Tumor Cells

Abstract

We report herein a gene-directed enzyme prodrug therapy (GDEPT) system using gated mesoporous silica nanoparticles (MSNs) in an attempt to combine the reduction of side effects characteristic of GDEPT with improved pharmacokinetics promoted by gated MSNs. The system consists of the transfection of cancer cells with a plasmid controlled by the cytomegalovirus promoter, which promotes β-galactosidase (β-gal) expression from the bacterial gene lacZ (CMV-lacZ). Moreover, dendrimer-like mesoporous silica nanoparticles (DMSNs) are loaded with the prodrug doxorubicin modified with a galactose unit through a self-immolative group (DOXO-Gal) and modified with a disulfide-containing polyethyleneglycol gatekeeper. Once in tumor cells, the reducing environment induces disulfide bond rupture in the gatekeeper with the subsequent DOXO-Gal delivery, which is enzymatically converted by β-gal into the cytotoxic doxorubicin drug, causing cell death. The combined treatment of the pair enzyme/DMSNs-prodrug are more effective in killing cells than the free prodrug DOXO-Gal alone in cells transfected with β-gal.

Synthesis of Mesoporous Silica Using the Sol–Gel Approach: Adjusting Architecture and Composition for Novel Applications

“…Subsequently, additional functional elements, such as Ca 2+ , -S-S-, and PEG, are introduced onto the surface of mesoporous silica to establish a delivery response to pH, GSH, temperature, etc. (see Table 1 ) [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. In recent years, enhancing therapeutic effects has led to a focus on constructing multifunctional drug delivery platforms.…”

Glycosidase activated prodrugs for targeted cancer therapy

“…The combined treatment of β-galactosidase transfected cells and the DMSNs-prodrugs resulted in a more effective therapy than that observed for the prodrug alone. 111…”

Photodynamic and Photothermal Therapy of Hepatocellular Carcinoma

“…MSNs are widely used because of their high specific surface area, controllable shape and easy surface functionalization ( 68 , 69 ). Silica nanoparticles have a sharp surface, which has strong plasmid DNA binding ability and transfection performance ( 70 ).…”