Dexamethasone-Appended Activatable Prodrug Overcoming Multidrug Resistance.

Residual tumor cells that persist after chemotherapy, even in minimal quantities, often exhibit drug resistance and increased invasiveness, potentially leading to tumor metastasis and recurrence. This study introduces a novel reactive oxygen species (ROS)-responsive prodrug, Dex-Dox, designed to overcome multidrug resistance (MDR) in tumor cells. The prodrug is composed of the anti-inflammatory glucocorticoid dexamethasone (Dex) conjugated with doxorubicin (Dox), a widely used antitumor agent, through an oxidative stress-responsive linker. Our in vitro findings revealed that, while Dex alone did not exhibit antitumor activity, Dex-Dox significantly enhanced drug sensitivity, promoting apoptosis and inhibiting angiogenesis in drug-resistant cells. Furthermore, in vivo therapeutic evaluations and histological analyses demonstrated that Dex-Dox substantially reduced tumor volumes, especially in a Dox-resistant tumor mouse model, underscoring its potential as an effective strategy against MDR in cancer therapy.