Enhanced doxorubicin transport to multidrug resistant breast cancer cells via TiO 2 nanocarriers† Wenzhi Ren, a Leyong Zeng, a Zheyu Shen, a Lingchao Xiang, a An Gong, a Jichao Zhang, b Chengwen Mao, b Aiguo Li, b Tatjana Paunesku, c Gayle E. Woloschak, c Narayan S. Hosmane d and Aiguo Wu‡ * a In order to overcome the multidrug resistance of breast cancer cells, doxorubicin was loaded onto TiO 2 nanoparticles in which the electrostatic interactions hold the drug and the nanoparticles together. The anticancer activity of this nanocomposite was evaluated in multidrug resistant breast cancer cells. In nanocomposite treated MCF-7/ADM cells, drug accumulation increased with enhanced anticancer activity about 2.4 times compared to that of doxorubicin alone. The potential mechanism of enhanced drug accumulation is ascribed to the fact that the nanocomposite directly transports the drugs into cells via internalization, bypassing the P-glycoprotein mediated doxorubicin pumping system. Our results reinforce that the nanocomposite, as a pH controlled drug release system, could be used to overcome multidrug resistance of human breast cancer cells. 1. Introduction Chemotherapy is a major clinical approach for treatment of malignant tumors, but multidrug resistance of cancer cells is a major cause of failure in chemotherapy. 1 Over expression of P- glycoprotein (P-gp) on the membrane of cancer cells is consid- ered to be the main mechanism of multidrug resistance. 2 It has been shown that P-gp can pump the drugs out, thus reducing intracellular drugs accumulation and weakening the anticancer effect of drugs. 3 The development of nanotechnology-driven drug delivery has the potential to revolutionize cancer therapy. 4,5 It has also been suggested that nanoparticle-based drug delivery may be able to circumvent P-glycoprotein mediated drug resistance in cancer and, consequently, reversing multidrug resistance. 6 Recently, a variety of inorganic nanocarriers, such as iron oxide nanoparticles, mesoporous silica nanoparticles, graphene oxide and titanium dioxide nanoparticles have been studied for drug delivery and therapy in multidrug resistant cancers. 7–12 TiO 2 nanoparticle is a potential dynamic therapy agent in cancer therapy due to excellent biocompatibility and its unique photocatalytic properties. 13,14 Recently, our group has synthesized multifunctional Fe 3 O 4 –TiO 2 nanocomposite for potential applications in both magnetic resonance imaging (Fe 3 O 4 constituent) and inorganic photodynamic therapy (TiO 2 constituent). 15 In addition, TiO 2 nanoparticles have also received much attention in the eld of drug delivery of chemotherapeutic agents. Yan Chen et al. constructed DOX– TiO 2 composite as a drug delivery system. 16 The results show that this drug delivery system markedly increased the anti- cancer efficiency of the drug per dose in human SMMC-7721 hepatocarcinoma cells. In another study reported by Ying Qin et al., TiO 2 -loaded DOX was prepared by non-covalent complexation (TiO 2 /DOX) and/or covalent conjugation (TiO 2 – DOX). The therapeutic efficacy of two different loading modes was evaluated in C6 glioma cells. The results show that non- covalent TiO 2 /DOX composite exhibited an increased cytotox- icity toward C6 cells compared to that of DOX alone, while the covalent composite of TiO 2 /DOX showed decreased cytotox- icity. 17 The study indicates that the therapeutic efficacy is strongly dependent on its nature of interaction between TiO 2 nanoparticle surface and loaded DOX, which provides impor- tant information for the future applications of TiO 2 nano- particles as drug carriers. In our recent work, the Fe 3 O 4 @TiO 2 core–shell nano- composites with 6–8 nm diameter have been explored as carriers for DOX delivery in drug-resistant ovarian carcinoma cells. 12 Accordingly, the DOX was loaded on TiO 2 surface by a labile a Key Laboratory of Magnetic Materials and Devices & Division of Functional Materials and Nanodevices, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, Ningbo, 315201, China b Shanghai Synchrotron Radiation Facility, Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai, 201204, China c Department of Radiation Oncology, Northwestern University Feinberg School of Medicine Chicago, Illinois, 60611, USA d Department of Chemistry & Biochemistry, Northern Illinois University DeKalb, Illinois, 60115-2862, USA † Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra42863j ‡ Present address: Room A510, No. 519 Zhuangshi Road, Ningbo City, Zhejiang Province, 315201, China, E-mail address: aiguo@nimte.ac.cn, Fax: +86 574 86685163, Tel: +86 574 86685039. Cite this: RSC Adv., 2013, 3, 20855 Received 9th June 2013 Accepted 21st August 2013 DOI: 10.1039/c3ra42863j www.rsc.org/advances This journal is ª The Royal Society of Chemistry 2013 RSC Adv., 2013, 3, 20855–20861 | 20855 RSC Advances PAPER