A Novel Targeted Co-Delivery Nanosystem for Enhanced Ovarian Cancer Treatment Via Multidrug Resistance Reversion

Abstract

Multidrug resistance (MDR) is a major challenge in successful chemotherapy treatment of ovarian cancer patients, and 50%–75% of ovarian cancer patients eventually relapse because of MDR. One of an effective strategy for treating MDR and improving therapeutic efficiency of ovarian cancer is to use nanotechnology-based targeted drug delivery systems. This study developed a novel hyaluronic acid (HA)-targeted co-delivery nanosystem using functionalized mesoporous silica nanoparticle–coated gold nanorods (HA-PTX/let-7a-GNR@MSN) to co-deliver paclitaxel (PTX), a hydrophobic chemotherapy drug, and lethal-7a (let-7a), a microRNA (miR), to overcome MDR in ovarian cancer. We also analyzed the molecular mechanism of miR let-7a in ovarian cancer treatment. The nanosystem enabled protective drug delivery and stable binding of PTX and miRs. Analysis of drug-resistant SKOV3TR cells and an SKOV3TR xenograft model in BALB/c-nude mice showed significant P-glycoprotein downregulation in heterogeneous tumor sites, PTX release, and apoptosis induction later. Results showed that HA-modified nanocomposites can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3 TR cells, achieving effective cell uptake and 150% enhancement of tumor site permeability. More importantly, this nanosystem resulted in synergistic inhibition of ovarian tumor growth. Overall, the data provide a model for overcoming PTX resistance in ovarian cancer.