Dual‐Targeted Nanoreactors and Prodrugs: Hydrogen Peroxide Triggers Oxidative Damage and Prodrug Activation for Synergistic Elimination of Cancer Cells

Synergistic strategies by combining nanoreactors and prodrugs hold tremendous potential in anticancer treatment. However, precise death of target cancer cells remains a significant challenge due to the absence of an elaborate cancer targeting strategy. Here, a dual-targeting approach that combines the action of H2O2-producing folate receptor-targeted nanoreactors with a cyclooxygenase-2 (COX-2) targeted prodrug is reported. A folate-modified silica nanoreactor encapsulating glucose oxidase (GOX) is prepared to generate H2O2, which induces oxidative stress and allows the activation of the prodrug by targeted intracellular delivery. A novel prodrug bearing both COX-2 targeting Celecoxib and SN-38 anticancer agent with an H2O2-cleavable thioketal linker to activate the drug is presented. By dual-targeting, the generated H2O2 from GOX triggers the cleavage of a thioketal linker in the prodrug to produce the active form of the SN-38 anticancer drug in cancer cells inducing synergistic cell death. This dual-targeting strategy with a synergistic potency can aid in developing selective and effective anticancer therapeutics.