Nanocatalytic Theranostics with Glutathione Depletion and Enhanced Reactive Oxygen Species Generation for Efficient Cancer Therapy

TLDR

Chemodynamic therapy (CDT) kills cancer cells by converting intracellular hydrogen peroxide into highly toxic hydroxyl radicals. The study presents an intelligent nanocatalytic theranostic, PGC‑DOX, designed to supply H₂O₂ and eliminate glutathione for efficient cancer therapy. PGC‑DOX is fabricated by one‑step biomineralization of PEG‑modified glucose oxidase with copper‑doped calcium phosphate nanoparticles and loading doxorubicin, and glucose oxidase generates H₂O₂ while released Cu²⁺ depletes glutathione, reduces to Cu⁺ and catalyzes a Fenton‑like reaction that converts H₂O₂ into hydroxyl radicals, amplifying CDT. In vivo, the combined GOx‑mediated starvation, H₂O₂ self‑supply, GSH‑elimination enhanced CDT, and DOX chemotherapy produced effective tumor growth inhibition with minimal side effects.

Abstract

Chemodynamic therapy (CDT) is an emerging therapy method that kills cancer cells by converting intracellular hydrogen peroxide (H2 O2 ) into highly toxic hydroxyl radicals (• OH). To overcome the current limitations of the insufficient endogenous H2 O2 and the high concentration of glutathione (GSH) in tumor cells, an intelligent nanocatalytic theranostics (denoted as PGC-DOX) that possesses both H2 O2 self-supply and GSH-elimination properties for efficient cancer therapy is presented. This nanoplatform is constructed by a facile one-step biomineralization method using poly(ethylene glycol)-modified glucose oxidase (GOx) as a template to form biodegradable copper-doped calcium phosphate nanoparticles, followed by the loading of doxorubicin (DOX). As an enzyme catalyst, GOx can effectively catalyze intracellular glucose to generate H2 O2 , which not only starves the tumor cells, but also supplies H2 O2 for subsequent Fenton-like reaction. Meanwhile, the redox reaction between the released Cu2+ ions and intracellular GSH will induce GSH depletion and reduce Cu2+ to Fenton agent Cu+ ions, and then trigger the H2 O2 to generate • OH by a Cu+ -mediated Fenton-like reaction, resulting in enhanced CDT efficacy. The integration of GOx-mediated starvation therapy, H2 O2 self-supply and GSH-elimination enhanced CDT, and DOX-induced chemotherapy, endow the PGC-DOX with effective tumor growth inhibition with minimal side effects in vivo.