Tumor-targeting pH/redox dual-responsive nanosystem epigenetically reverses cancer drug resistance by co-delivering doxorubicin and GCN5 siRNA

ABSTRACT Multidrug resistance (MDR) is a major cause accounting for chemotherapy failure and recurrence of malignant tumors. A prominent mechanism underlying MDR is overexpression of P-glycoprotein (P-gp, a drug efflux pump). Promoting drug delivery efficacy by targeting tumor and concurrently suppressing drug efflux through down-regulating P-gp emerges as an effective strategy to enhance intracellular drug accumulation for combating MDR tumor. General Control Non-repressed 5 (GCN5), a histone acetyltransferase acting as an epigenetic regulator of multidrug resistance protein 1 (MDR1), positively regulates P-gp levels in drug-resistant cancer cells. Herein, a hyaluronic acid-coated, pH/redox dual-responsive nanosystem (HPMSNs) is fabricated for co-delivering doxorubicin (DOX) and GCN5 siRNA (siGCN5). This nanosystem can effectively encapsulate DOX and siRNA preventing premature leakage and releasing these therapeutics intracellularly via its pH/redox dual responsiveness. Through CD44-mediated targeting, DOX/siGCN5@HPMSNs increases drug internalization in CD44-overexpressing cancer cells, and markedly promotes DOX retention by down-regulating P-gp expression in drug-resistant cancers through silencing GCN5. Of note, in an MDR breast tumor model, DOX and siGCN5 co-delivered HPMSNs inhibits MDR tumor growth by 77%, abolishes P-gp-mediated drug resistance, and eliminates DOX's systemic toxicity. Thus, the tumor-targeting, stimuli-responsive nanosystem is an effective carrier for co-delivering anticancer drug and siRNA for combating cancer drug resistance. Statement of significance : We designed a tumor-targeting, pH/redox dual-responsive nanosystem (HPMSNs) for chemo-drug and siRNA co-delivery. This nanosystem efficiently co-delivered DOX and siGCN5 into drug-resistant cancer cells and significantly inhibited the tumor growth through: (1) HA shell enhanced the cellular internalization of loaded DOX and siGCN5 via CD44-mediated targeting; (2) the pH/redox dual-responsive nanosystem released the cargos in response to the intracellular environment; (3) the released siGCN5 downregulated P-gp epigenetically. In an MDR breast tumor model (MCF7/ADR), DOX and siGCN5 loaded HPMSNs markedly inhibited tumor growth, almost completely abolished P-gp expression, and minimized systemic toxicity of DOX.