A novel targeted co-delivery nanosystem for enhanced ovarian cancer treatment via multidrug resistance reversion and mTOR-mediated signaling pathway

Background: Multidrug resistance (MDR) is the main challenge of successful chemotherapy for ovarian cancer patients, with 50% to 75% of ovarian cancer patients eventually relapsed due to it. One of the effective strategies for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed by using gold nanorods coated with functionalized mesoporous silica nanoparticles (HA-PTX/let-7a-GNR@MSN) for combined delivery of hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. Furthermore, we also analyzed the molecular mechanism of this nanotherapeutic system in the treatment of ovarian cancer. Results: HA-modified nanocomplexes can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3m cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. The nanosystem realized the stable combination and protective transportation of PTX and miRs. Analysis of drug-resistant SKOV3(TR) cells and an SKOV3(TR) xenograft model in BALB/c-nude mice showed significant downregulation of P-glycoprotein in heterogeneous tumor sites, PTX release, and subsequent induction of apoptosis. More importantly, this nanosystem could synergistically inhibit the growth of ovarian tumors. Further studies suggest that mTOR-mediated signaling pathways play an important role in reversing drug resistance and inducing apoptosis. Conclusions: To sum up, these data provide a model for overcoming PTX resistance in ovarian cancer.

Automated summary

In this study, a novel nano targeted co-delivery system modified by hyaluronic acid (HA) was developed to overcome multidrug resistance in ovarian cancer by delivering hydrophobic chemotherapy drug Paclitaxel (PTX) and lethal-7a (let-7a) microRNA. The nanosystem demonstrated effective cell uptake and enhanced tumor site permeability, leading to downregulation of P-glycoprotein, PTX release, and apoptosis induction. Additionally, mTOR-mediated signaling pathways played a crucial role in reversing drug resistance and inducing apoptosis, providing a model for overcoming PTX resistance in ovarian cancer.