Quercetin and doxorubicin co-delivery using β-cyclodextrin nanocarrier overcomes multi-drug resistance in cancer cells via targeting Akt/NF-κB/ABCB1 signaling pathway

The overexpression of ATP-binding cassette (ABC) drug efflux transporters, notably P-glycoprotein (P-gp) encoded by ABCB1, significantly contributed to multi-drug resistance (MDR) in chemotherapy. This study investigated the potential of beta-cyclodextrin biopolymer for co-delivery of quercetin and doxorubicin nanocarriers (β-CDP/QD NCs) to bypass drug efflux in MDR cells. Calcein-AM assay revealed that quercetin inhibited P-gp transport function. Cell survival and migration assays demonstrated that β-CDP-encapsulated quercetin enhanced doxorubicin chemotherapeutic activity in MDR cells. Targeted drug-resistant cells showed enhanced intracellular ROS, DNA damage, and G2/M phase arrest in MDR cells due to improved DOX retention. Pharmacokinetic studies indicated an extended half-life and enhanced bioavailability of β-CDP/QD NCs. Additionally, quercetin attenuated Akt/NF-κB signaling, which downregulated ABCB1 overexpression in MDR cells. Thus, β-CDP/QD NCs modulated the ABCB1 efflux pump via the Akt/NF-κB/ABCB1 pathway, enhancing chemotherapy efficacy in MDR cells. Therefore, β-CDP could be considered a promising nanocarrier for delivering chemotherapeutic agents and ABCB1 modulators to overcome MDR.