Active Tumor Targeting by Core-Shell PDMS-HA Nanoparticles with Sequential Delivery of Doxorubicin and Quercetin to overcome P-glycoprotein efflux pump

Abstract

The therapeutic efficacy of chemotherapy in various malignancies and solid tumors is significantly limited when used as monotherapy. This study explored a combined treatment approach for breast cancer cells involving sequential delivery of doxorubicin followed by quercetin, both delivered via polydimethylsiloxane nanoparticles decorated with hyaluronic acid. Quercetin inhibits P-glycoprotein efflux action to enhance doxorubicin activity by increasing its intracellular accumulation; hence, both synergistically suppress cancer cell growth by promoting cytotoxicity and apoptosis. Quercetin reverses multidrug resistance, induces arrest in the cell cycle, and alters the mitochondrial membrane potential. The successful delivery and internalization of these drugs into breast cancer cells were confirmed through CD44 ligand recognition, inhibiting cell viability via apoptosis (caspase-induced) and cell arrest in the G2/M phase of the cell cycle. Furthermore, MCF-7 (breast cancer) cells-derived xenograft tumor model using NOD/SCID mice, the core-shell PDMS-HA nanoparticle system carrying quercetin and doxorubicin resulted in approximately 65% of tumor volume reduction, outperforming the loaded single drug and free drug combination. These results were supported by the TUNEL assay and proliferation index by Ki-67 immunohistochemistry staining, which shows substantial cell death and tissue necrosis in the tumor sections. Histological studies of tumor tissues confirm enhanced anticancer efficacy with negligible systemic toxicity to normal organs. Overall, the PDMS-HA delivery system efficiently transports quercetin and doxorubicin to tumor cells, enhancing the antitumor effects against the MCF-7 tumor xenograft model in mice without adverse effects. This study suggests that the targeted co-delivery of phytochemicals and anti-cancer agents can synergistically overcome many barriers associated with tumor treatment.