Temporal Dosing Tunes Glutathione Gradient across Liver-Blood-Tumor Axes to Boost the Chemotherapeutic Potency of Prodrug Nanoassemblies

Abstract Redox-responsive prodrug nanodelivery systems hold immense promise in cancer therapy, offering advantages of improved pharmacokinetics, enhanced tumor selectivity, and increased safety. However, compared with standard therapeutic formulations, prodrug nanodelivery systems fail to yield superior antitumor efficacy at equivalent doses, attributable to inadequate drug activation and intratumoral accumulation. Herein, the three-in-one drug-release module, comprising an α-disulfide bond, an ethylene glycol moiety, and a short carbon chain, was covalently linked to paclitaxel (PTX) to construct three prodrug nanoassemblies (PSBA10 NPs, PSBA12 NPs, PSBA14 NPs). Notably, PSBA10 NPs, which possessed the shortest carbon chain, exhibited hypersensitive redox-responsive drug release and potentiated antitumor efficacy. Although PSBA10 NPs exhibited better safety than paclitaxel solution (Taxol) at equivalent doses, superior efficacy remained unattainable. Interestingly, a temporal-dose-regulated glutathione (GSH) gradient across the liver-blood-tumor axis increased the intratumoral accumulation of PSBA10 NPs by approximately 3-fold, resulting in pronounced antitumor efficacy superior to Taxol. This transient depletion of GSH in the liver and blood reduced the cleavage of disulfide bonds in the systemic circulation, enhancing tumor accumulation and selective activation of PSBA10 NPs. Our study highlighted a tumor treatment model based on the synergistic strategy of structural optimization and GSH gradient regulation across the liver-blood-tumor axis to boost the efficacy of chemotherapy.