Nanoceria-mediated delivery of doxorubicin enhances the anti-tumour efficiency in ovarian cancer cells via apoptosis

Jin-Hoi Kim,Joydeep Das,Jae Woong Han,Abu Musa Md Talimur Reza,Yun-Jung Choi

doi:10.1038/s41598-017-09876-w

Abstract

Nanocarriers are widely used for effective delivery of anticancer drugs to tumours with potential to improve cancer treatment. Here, we developed a nanoceria (CeO2)-based system for delivery of the anti-cancer drug doxorubicin (DOX) to human ovarian cancer cells. Negatively charged nanoceria could conjugate with the cationic DOX via electrostatic interaction under physiological conditions, forming DOX-loaded nanoceria (CeO2/DOX). CeO2/DOX particles displayed nearly spherical shapes, along with superior drug-loading content (22.41%), loading efficiency (99.51%), and higher cellular uptake and drug release behaviours compared to free DOX. Moreover, DOX was released faster from CeO2/DOX under reductive acidic conditions (pH 5.0, 10 mM glutathione) than under physiological conditions (pH 7.4). The initial intracellular DOX concentration was higher in the free DOX groups than in the CeO2/DOX groups, but quickly reduced to 25% of the initial concentration after 24-h culture. By contrast, CeO2/DOX showed sustained DOX release over time and maintained a high intracellular DOX concentration for up to 72 h. In vitro assays showed that CeO2/DOX exhibited higher cell proliferation inhibition and apoptosis compared with free DOX. These results highlight DOX-loaded nanoceria as a promising therapeutic agent for cancer treatment.

Highlights

Ovarian cancer is the fifth most prevalent cancer among women causing death and is the most lethal gynaecologic malignancy, mainly owing to late-stage diagnosis
The nanoceria were further examined by X-ray photoelectron spectroscopy (XPS) to determine the different valence states
McCormack et al.[33] reported that nanoceria with higher percentage of surface Ce+3 oxidation states are more prone to interact with phosphate ions and forming cerium phosphate, thereby influencing the catalytic activities of nanoceria

Summary

Introduction

Ovarian cancer is the fifth most prevalent cancer among women causing death and is the most lethal gynaecologic malignancy, mainly owing to late-stage diagnosis. The same group[21] later showed that folic acid-conjugated nanoceria (FA-CeO2 containing 24% Ce3+) inhibited ovarian cancer cell proliferation (due to increased cellular uptake) and increased ROS production. Despite these differences in its pro- or anti-oxidant nature, both studies demonstrated an association of nanoceria with significant reduction in tumour growth and attenuation of angiogenesis in an ovarian cancer nude mouse model. They showed that the combination of FA-CeO2 with cisplatin decreased the tumour burden significantly, even compared to the cisplatin alone-treated group. We propose that high anticancer efficiency can be achieved by combining the advantages of DOX as a conventional chemotherapeutic drug and the anti-tumorigenic nature of nanoceria to prepare a one-particle system (CeO2/DOX)

Methods

Results

Conclusion