Colloids and Surfaces B: Biointerfaces 113 (2014) 249–253 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces jou rn al hom epage: www.elsevier.com/locate/colsurfb Enhanced doxorubicin delivery and cytotoxicity in multidrug resistant cancer cells using multifunctional magnetic nanoparticles Chalermchai Pilapong a,∗ , Yanee Keereeta b , Samlee Munkhetkorn a , Somchai Thongtem b , Titipun Thongtem c a Center of Excellence for Molecular Imaging (CEMI), Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai 50200, Thailand b Department of Physics and Material Science, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand c Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand a r t i c l e i n f o Article history: Received 4 June 2013 Received in revised form 30 August 2013 Accepted 3 September 2013 Available online 18 September 2013 Keywords: Magnetic nanoparticles Multidrug resistance pH-Dependent drug release Doxorubicin a b s t r a c t Carboxymethyl modified magnetic nanoparticles (CMC-MNPs) have been designed as a vehicle for drug delivery in both drug-sensitive and drug-resistant cancer cells. We have demonstrated that the CMC- MNPs were able to load doxorubicin (DOX) with a high loading efficiency while also maintaining a good colloidal stability in an aqueous solution. According to a drug release study, DOX-loaded CMC- MNPs showed that the pH-dependent drug release property had a much higher release rate in acidic pH. Compared to free DOX, the DOX-loaded CMC-MNPs showed higher DOX accumulation in drug-sensitive cancer cells and much higher accumulation in drug-resistant cancer cells. These results indicate that our nanoplatform is highly efficient as a drug delivery system in both normal cancer cells and MDR cancer cells. In addition, the DOX-loaded CMC-MNPs can also enhance cytotoxicity against drug-resistant cancer cells in comparison to free DOX. The results obtained in this research demonstrate that our nanoplatform may be a promising approach in cancer chemotherapy and for overcoming multidrug-resistant cancer cells. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Cancer is a leading cause of death worldwide [1], with an estimated 13.1 million deaths in 2030 [2]. Approximately 50% of human cancer treatment is based on chemotherapy. However, the major limitation of this method is multidrug resistance (MDR) [3,4]. Generally, MDR reflects an overexpression of ATP-binding cassette (ABC) transporters on cellular membrane, for example, P-glycoprotein (P-gp), multidrug resistant protein-1 (MRP1), and breast cancer resistant protein (BCRP), which are capable of causing various anticancer drugs such as doxorubicine (DOX), pirarubicin, and paclitaxel to efflux [5–8]. Subsequently, overcoming of MDR in human cancer has become a hot topic in anticancer research. There are several early strategies to overcome MDR in cancer, includ- ing a modification of the chemotherapy regime, inactivation of the MDR-associated genes, development of new anticancer drugs, and the use of ABC transporter inhibitors [9,10]. Among these, the development of the ABC transporter inhibitors has received much attention. However, several limitations, including unacceptable cytotoxicity and unwanted pharmacokinetic interaction between ∗ Corresponding author. Tel.: +66858661303. E-mail address: chalermchai.pilapong@cmu.ac.th (C. Pilapong). the inhibitors and the chemotherapeutics, have prevented their successful translation from research to clinical usage [11–15]. Recently, nanotechnology-based formulations, or nanomedicine, have shown promise as a strategy for cancer treatment because this approach not only provides a new opportunity to over- come MDR cancer cells [9,10,16] but also shows multifunctional platforms for cancer treatment such as theranostics by encapsu- lating, attaching, and conjugating drugs or specific biomolecules to the nanocarriers[17–21]. Various types of nanocarriers have been developed as multifunctional nanoplatforms for overcoming the MDR cells, such as lipid, polymer, silica, and magnetic nanoparticles [22–26]. These can confirm that encapsulating drugs in nanocar- riers has a potential for overcoming MDR. On the other hand, it is well known that pH values vary significantly in different tissue and cellular compartments [27]. The healthy tissues have a normal physiological pH of ∼7.4, whereas the extracellular environment of a tumor exhibits a lower pH (∼6.8) and even lower in intracellular endosomal/lysosomal compartments (∼4.5–5.5). Therefore, pH can be utilized as a useful strategy for cancer targeting [28]. Presently, we have developed a multifunctional nanocarrier which is not only used to overcome MDR but also has pH-responsive drug release behavior. The nanocarrier is composed of magnetic iron oxide nanoparticles (MNPs) coated with carboxymethyl cellu- lose (CMC). The MNPs were employed as vehicles for drug delivery 0927-7765/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.colsurfb.2013.09.005