A GSH-responsive oxidative stress nanoamplifier for self-augmented chemo/chemodynamic therapy to reverse cisplatin resistance

Drug resistance and off-target toxicity of cisplatin (CDDP) pose significant challenges in effectively treating non-small cell lung cancer (NSCLC). Recently, chemodynamic therapy (CDT), an emerging reactive oxygen species (ROS)-mediated tumor-specific therapeutic modality, has shown great potential in sensitizing multidrug resistance tumor cells. Herein, a glutathione (GSH)-responsive Pt(IV) prodrug-based oxidative stress nanoamplifier (CuBSO@Pt_C16) was developed for effective chemo/chemodynamic therapy to reverse CDDP resistance in NSCLC. CuBSO@Pt_C16, a lipid-coated nanoagent, was constructed by coordinating Cu²⁺ with l-buthioninesulfoximine (BSO) as the core framework, and Pt(IV) prodrug (Pt_C16) was concurrently loaded on the outer lipid bilayer. With appropriate particle size (∼35 nm) and good physiological stability, CuBSO@Pt_C16 efficiently accumulated at tumor tissue. Under high intracellular GSH levels, Pt_C16 was reduced to generate cytotoxic CDDP that induced cell-killing and boosted intracellular H₂O₂ levels, and the CuBSO core was disassembled to release Cu ions and BSO simultaneously. The released BSO could efficiently reduce the intracellular GSH content to weaken its detoxification effect on CDDP, leading to more Pt-DNA adduct formation and more severe DNA damage. Meanwhile, Cu ions catalyzed the intracellular elevated H₂O₂ into highly lethal •OH through Fenton-like reactions, and the reduction of GSH weakened the •OH elimination, which jointly amplified the intracellular oxidative stress levels, finally achieving enhanced chemo/chemodynamic therapeutic effect and reversing CDDP resistance in NSCLC. Therefore, this work offers an inspirational idea for effectively treating drug-resistant cancers.

Statement of significance

Cisplatin (CDDP) faces challenges in treating non-small cell lung cancer (NSCLC) due to drug resistance and off-target toxicity. Herein, a GSH-responsive nanoreactor (CuBSO@Pt_C16) was developed for effective chemo/chemodynamic therapy to address CDDP resistance. CuBSO@Pt_C16 could efficiently traffic to tumor site and response to high GSH levels in tumor cells to release CDDP, Cu ions and buthioninesulfoximine (BSO) simultaneously. CDDP could induce DNA damage and boost intracellular H₂O₂ levels, which then served as the substrate of Cu to induce •OH generation through Fenton-like reactions. Meanwhile, the released BSO efficiently reduced the intracellular GSH content to weaken its detoxification effect on CDDP and the elimination of the •OH, leading to amplified intracellular oxidative stress and more severe damage to induce cell death.