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.
Highlights
Cancer disease causes high mortality and morbidity around the world
We developed a combined system following a gene-directed enzyme prodrug therapy (GDEPT) approach (β-gal and DOXO-Gal as an enzyme-prodrug pair) and the encapsulation of the prodrug (DOXOGal) in dendrimer-like mesoporous silica nanoparticles (MSNs), which were capped with a disulfide-containing polyethyleneglycol gatekeeper
The prodrug DOXO-Gal remained in the dendrimer-like mesoporous silica nanoparticles (DMSNs) until the addition of GSH, which promoted the rupture of the disulfide bonds and subsequent cargo release
Summary
Cancer disease causes high mortality and morbidity around the world. There is a large variability between cancer of different patients and even between cells in a tumor [1,2]. Many tumor types can be efficiently cured, especially if they are diagnosed in early stages [3]. There are still several tumor types without a known effective treatment. Drugs used in chemotherapy have a restricted therapeutic index and high drug’s doses cannot be administered to patients without important undesired side effects. The pharmacokinetic profile of hydrophobic drugs is not efficient, as they tend to accumulate in adipose tissue and derived organs or to be sequestered in Nanomaterials 2021, 11, 1298.
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