A Novel Magnetic Nanoparticle Drug Carrier for Enhanced Cancer Chemotherapy Xu Chao1,5., Zhuoli Zhang3., Lili Guo2, Jingjing Zhu 4 , Mingli Peng 2 , Alphonsus J. M. Vermorken4, Wim J. M. Van de Ven4, Chao Chen1,2, Yali Cui1,2* 1 The College of Life Sciences, Northwest University, Xi’an, China, 2 National Engineering Research Center for Miniaturized Detection Systems, Xi’an, China, 3 Department of Radiology, Northwestern University, Chicago, Illinois, United States of America, 4 Laboratory for Molecular Oncology, Department of Human Genetics, K.U. Leuven, Leuven, Belgium, 5 The College of Basic Medical Science, Shaanxi University of Chinese Medicine, Xianyang, China Abstract Background: Magnetic nanoparticles (NPs) loaded with antitumor drugs in combination with an external magnetic field (EMF)-guided delivery can improve the efficacy of treatment and may decrease serious side effects. The purpose of this study was 1) to investigate application of PEG modified GMNPs (PGMNPs) as a drug carrier of the chemotherapy compound doxorubicin (DOX) in vitro; 2) to evaluate the therapeutic efficiency of DOX-conjugated PGMNPs (DOX-PGMNPs) using an EMF-guided delivery in vivo. Methods: First, DOX-PGMNPs were synthesized and the cytotoxicity of DOX-PGMNPs was assessed in vitro. Second, upon intravenous administration of DOX-PMGPNs to H22 hepatoma cell tumor-bearing mice, the DOX biodistribution in different organs (tissues) was measured. The antitumor activity was evaluated using different treatment strategies such as DOX- PMGPNs or DOX-PMGPNs with an EMF-guided delivery (DOX-PGMNPs-M). Results: The relative tumor volumes in DOX-PGMNPs-M, DOX-PGMNPs, and DOX groups were 5.4661.48, 9.2261.51, and 14.861.64, respectively (each p,0.05), following treatment for 33 days. The life span of tumor-bearing mice treated with DOX-PGMNPs-M, DOX-PGMNPs, and DOX were 74.869.95, 66.1613.5, and 31.363.31 days, respectively (each p,0.05). Conclusion: This simple and adaptive nanoparticle design may accommodate chemotherapy for drug delivery optimization and in vivo drug-target definition in system biology profiling, increasing the margin of safety in treatment of cancers in the near future. Citation: Chao X, Zhang Z, Guo L, Zhu J, Peng M, et al. (2012) A Novel Magnetic Nanoparticle Drug Carrier for Enhanced Cancer Chemotherapy. PLoS ONE 7(10): e40388. doi:10.1371/journal.pone.0040388 Editor: Efstathios Karathanasis, Case Western Reserve University, United States of America Received January 15, 2012; Accepted June 6, 2012; Published October 8, 2012 Copyright: 2012 Chao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National High Technology Research and Development (863) Program of China (2006AA020705). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: yali_cui@mail.com . These authors contributed equally to this work. Introduction Conventional chemotherapeutic compounds are distributed nonspecifically in the body, thus indiscriminately affecting both normal healthy cells as well as rapidly proliferating cancer cells. For this reason, for the desired therapeutic dose to reach the tumor, side effects occur in most cases due to high toxicity levels. The lack of targeting specificity of conventional chemotherapeutic agents makes magnetic nanoparticles (MNPs) attractive drug nanocarriers. For example, chemotherapeutic compounds may be conjugated with MNPs and can be specifically targeted to localized tumors by an external magnetic field (EMF)-guided delivery in vivo [1,2]. MNPs are being extensively investigated for use as drug carriers [3,4]. An EMF is placed and focused over the target site (i.e., the tumor or tumors). The direction of the EMF force allows nanoparticle/therapeutic agent complexes that are administered via intravenous or intra-artery injection to enter the tumor area. The EMF-guided drug enhances localized therapeutic efficacy of conjugated drugs and decreases systemic toxicity [1,4,5]. Gold nanoparticles have been used as carriers to investigate tumor, targeted drug delivery and laser treatment of cancer because of its better compatibility and circulation [6–8]. On the other hand, MNPs cooperated with polymer have been proved to be an attractive carrier as drug delivery vehicle [9]. These MNPs could not only couple drug on its surface, but also response to an EMF. Fe3O4/Au nanoparticles (GoldMag NPs/GMNPs) have a core/shell structure that is synthesized by the reduction of Au3+ with hydroxylamine in the presence of Fe3O4 [10,11]. As a result, GMNPs become magnetized, thus making particles responsive to subsequently applied magnetic fields due to the Fe3O4 core. Moreover, biomolecules (e.g., antibodies, antigens, and some chemotherapeutic compounds) can be readily coupled to the surface of these GMNPs without the need for additional cross- linkers [12–16]. Plasma proteins adsorbed on nanoparticles are rapidly removed by the reticuloendothelial system (RES) [17–20]. PLOS ONE | www.plosone.org 1 October 2012 | Volume 7 | Issue 10 | e40388