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  • br Introduction and disease progression in


    1. Introduction and disease progression in many types of cancers, finding and mon-
    itoring these cancerous cells seems to be critical [5,6]. In addition, Cancer is the second leading cause of death, and is a major public isolating CTCs can provide a valuable source of metastasizing tumor health issue worldwide [1]. The latest worldwide cancer statistics es- cells for further molecular analysis as well as the development of new timate that around 18.1 million new cases will have been diagnosed by targeted drugs. In this regard, much effort has recently been directed the end of 2018. Breast cancer (BC) is considered the most frequently towards developing efficient techniques for the identification and diagnosed type (24.2% of all cancers) and the leading cause of cancer quantification of tumor cells in the blood stream using immunolabels deaths (15% of all cancers) among women. Approximately 2,088,849 specific to epithelial cell markers, e.g. HER2, EpCAM or different cy- new cases are expected to be diagnosed, and 626,679 deaths are pre- tokeratins [7,8]. dicted, which indicates a significant increase of 19.7% and 16.7% re- Target-specific separation of cancer cells, a common method for cell spectively compared to 2012 [2,3]. detection and separation could be improved by the conjugation of It is well established that timely screening followed by early diag- targeting moieties i.e. specific 2-NBDG on the surface of separation nosis will have several positive outcomes including saving lives in systems [9–11]. The use of targeting ligands enhances specificity, in- general, choosing the most effective treatment, and collectively redu- creases adhesion and intracellular delivery of nanosystems, and more cing costs. Specifically in relation to BC, advances in early detection and importantly, increases local concentration at the target site [11]. Cur- treatment have significantly reduced the death rate in recent years [4]. rently, in the field of biotechnology and bio-nanomedicine, bio-func- New technologies have provided opportunities for earlier diagnosis tionalized magnetic nanoparticles (MNPs), especially iron oxide MNPs, as well as the detection of circulating tumor cells (CTCs) [4]. Because have advantages due to their widespread use [12–16]. Magnetite is the number of CTCs is a valuable prognostic factor for patients’ survival attracting attention for bioseparation, because of its super-
    Corresponding author.
    E-mail address: [email protected] (M.T. Khorasani).
    Fig. 1. Magnetic measurement of nanoparticles with (MNP-Si) and without APTES coating (MNP) in VSM assays. Inset: Magnetization curve in a low magnetic field.
    paramagnetic properties, non-toxicity, high surface area, low price and different production methods, which can be adapted to the requisite characteristics for specific applications. Their high potential for mod-ification and customization along with their biocompatibility has led to the increasing use of iron oxide MNPs in bioseparation therapeutics and diagnostics [17–23]. Concordantly, antibody-conjugated nanoparticles are among the MNPs that are extensively used for a variety of purposes including the diagnosis and treatment of different cancers [24,25], magnetic resonance imaging [26,27], hyperthermia and magnetic se-paration [28–31], purification, and immunoassays [15,32]. Accord-ingly, in the present study, Fe3O4 MNPs ranging in diameter between 20 and 30 nm were coated with (3-aminopropyl) trimethoxysilane (APTES) and investigated as a cell separation vehicle.
    Bare-surface MNPs are hydrophobic and unsuitable for 
    immobilizing biological substances such as low-molecular-weight li-gands, proteins and peptides [33,34]. Various coating materials are available, e.g. natural dispersants, surfactants, polymers and silane, which are commonly used for iron surface modification [13]. In this study, silane was selected to coat the surface of MNPs due to its special characteristics [35,36]. Unlike polymers, silane is a chemically inert substance that does not induce side effect at the nanoparticle core [37–39]. Changes in environmental pH do not affect the porosity or lead to shell swelling; consequently the core properties do not change and the core is not oxidized thanks to the stabilizing effects of silane. Moreover, because the shell is nonmagnetic, bipolar interactions of the particles as well as agglomeration are avoided, make silane a suitable coating material. Additionally, silane has functional groups which can form covalent bonds with other functional groups, making further
    Fig. 3. FT-IR spectra of MNPs with and without APTES.