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

Xueqin Wang,Yunlong Wang,Tiandi Xiong,Yuqi Guo,Miao Cui,Shaofeng Duan,Li Zhu,Qin Li,Na Li

doi:10.1186/s12951-021-01139-1

Abstract

BackgroundMultidrug 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.ResultsHA-modified nanocomplexes can specifically bind to the CD44 receptor, which is highly expressed in SKOV3/SKOV3TR 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 SKOV3TR cells and an SKOV3TR 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.ConclusionsTo sum up, these data provide a model for overcoming PTX resistance in ovarian cancer.Graphical

Highlights

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
Synthesis and characterization of hyaluronic acid (HA)‐Polyethylene glycol-modified gold nanorods (pGNR)@Mesoporous silica nanoparticle (MSN) we report a novel HA-modified targeted nano drug delivery system that uses functionalized mesoporous silica nanoparticle-coated gold nanorods (HA-Gold nanorods (GNR)@MSN) to co-deliver PTX and miR let-7a to overcome MDR in ovarian cancer
The synthesis procedure of the targeted nanosystem is shown in Scheme 1, which includes: (i) synthesis of GNRs utilizing improved seed growth method; (ii) encapsulation of GNR with mesoporous silicon shells with large aperture to to load PTX and miR let-7a by aperture adsorption and electrostatic shielding method; (iii) amine modification with APTES; (iv) loading PTX and miR let-7a into silicon pores; (v) modification with NH2-polyethylene glycol (PEG)-COOH; and (vi) conjugation of this nanocomposite with HA via 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/NHS to forme a targeted Nano delivery system (HA-PTX/let-7a-GNR@MSN) to effectively enhance ovarian cancer treatment through multidrug resistance reversal

Summary

Introduction

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. Multidrug resistance (MDR) leads to poor effect or even failure of chemotherapy, and 50–75% of ovarian cancer patients eventually relapse because of MDR [3,4,5,6]. The high expression of MDR-related genes in ovarian tumor cells is the main cause of MDR in ovarian cancer [7, 8]. MDR1 inhibitors have been used for decades, their clinical effect is not sufficient enough to effectively reverse the MDR in ovarian cancer and improve prognosis. It is very important to find a way to reverse MDR in ovarian cancer

Methods

Results

Conclusion