Superparamagnetic iron oxide nanoparticles (SPIONs) are considered as chemically inert materials and, therefore, being extensively applied in the areas of imaging, targeting, drug delivery and biosensors. Their unique properties such as low toxicity, biocompatibility, potent magnetic and catalytic behavior and superior role in multifunctional modalities have epitomized them as an appropriate candidate for biomedical applications. Recent developments in the area of materials sci- ence have enabled the facile synthesis of Iron oxide nanoparticles (IONPs) offering easy tuning of surface properties and surface functionalization with desired biomolecules. Such developments have enabled IONPs to be easily accommodated in nanocomposite platform or devices. Additionally, the tag of biocompatible material has realized their potential in myriad applications of nanomedicines including imaging modalities, sensing, and therapeutics. Further, IONPs enzyme mimetic activity pronounced their role as nanozymes in detecting biomolecules like glucose, and cholesterol etc. Hence, based on their versatile applications in biomedicine, the present review article focusses on the current trends, developments and future prospects of IONPs in MRI, hyperthermia, photothermal therapy, biomolecules detection, chemotherapy, antimicrobial activity and also their role as the multifunctional agent in diagnosis and nanomedicines. Keywords Magnetic resonance imaging · Feraheme · Theranostics · Computed tomography · Cell labeling · Nanozymes · Magnetic separation Introduction of IONPs make them an excellent candidate for biomedical applications (Huang et al. 2009; Isa Karimzadeh 2017). IONPs possess unique properties, which are used to display Fe O NPs differ from other IONPs due to the presence 3 4 2+ 3+ several applications in biomedicine such as diagnostics, of both F e and F e combinations, where divalent ions imaging, hyperthermia, magnetic separation, cell prolif- are organized at the octahedral sites and trivalent ions are eration, tissue repair and drug delivery. Although nano- split across the tetrahedral and octahedral sites. However, 3+ structures of iron, cobalt, and nickel are known to exhibit α-Fe O contains F e ions distributed at their octahedral 2 3 superparamagnetic properties and high magnetic susceptibil- sites and in case of γ-Fe O (termed oxidized magnetite), 2 3 3+ ity, IONPs such as magnetite (F e O ), hematite (α-Fe O ) Fe cations are distributed in octahedral and tetrahedral 3 4 2 3 2+ and maghemite (γ-Fe O ), are the most studied magnetic sites along with F e cation vacancies located at octahedral 2 3 nanoparticle type. Owing to this property, IONPs display sites (Wu et al. 2015b). Due to their feasible polymorphism aggregation behavior under the magnetic field, which can be and their electron hopping nature, these IONPs were classi- suspended again as a stable suspension after removal of the fied as potential candidates in both biological and technical external magnetic field. In addition, the better colloidal sta- applications. In recent years, to enhance the use of IONPs in bility, biocompatibility, and persistence magnetic properties advanced applications/technologies NPs are altered by the creation of active layers supported by polymers, inorganic metal/metal oxides or bioactive molecules (Gupta and Gupta * Sanjay Singh 2005). The surface engineering of IONPs can be achieved by email@example.com several methods through layering a coating material over the Division of Biological and Life Sciences, School of Arts iron oxide core, to form core–shell structure or the NPs are and Sciences, Ahmedabad University Central Campus, dispersed in a matrix to form the beads (Gupta et al. 2007). Navrangpura, Ahmedabad, Gujarat 380009, India Vol.:(0123456789) 1 3 279 Page 2 of 23 3 Biotech (2018) 8:279 In addition, a Janus structure can be formed with one-half of perfluorocarbon emulsions, etc. (Emily and Waters 2008; IONPs and the rest with functional material, further, IONPs Liu et al. 2017). Further, IONPs are prepared in combination are embedded between two functional materials to form a with other NPs, proteins or dyes to achieve multiple appli- shell–core–shell structure (Wu et al. 2015b). cations in a single stage, for instance, MRI and immuno- Several methods like thermal decomposition, co-pre- histochemical staining of cancer cells was executed using cipitation, sol–gel, microemulsion, hydro-thermal, sono- ferrimagnetic H-ferritin (M-HFn) nanoparticles, dual MRI chemical, microwave, electrochemical and biosynthesis were and CT imaging of tumor was simultaneously fulfilled by evolved to synthesize IONPs (Huber 2005; Wu et al. 2015b). assembling gold (Au) nanocages‚ F e O NPs and triple 3 4 However, the relation between size, shape, and magnetism functional iron oxide nanoparticles (Fig. 1) with Cy5.5 dye in IONPs plays a crucial role in exhibiting their properties. and Cu-DOTA chelate were developed for MRI, positron For instance, F e O and F e O NPs display different fer - emission tomography (PET) and near-infrared fluorescence 2 3 3 4 rimagnetism at room temperature. Further, IONPs tend to (NIRF) imaging (Cai et al. 2015; Wang et al. 2016; Xie lose their dispersity after long-term due to aggregation of et al. 2010). particles and their magnetism gets diminished due to oxida- Ferumoxytol (Feraheme) is one of the types of magnetic tion in air. Thus different approaches are implemented to IONPs approved by the US Food and Drug Administration stabilize the NPs in an inert atmosphere and also to make (FDA) for the treatment of patients suffering from iron defi- them water-soluble at physiological pH, for applications in ciency with chronic kidney disease (CKD). It consists of a nanomedicine (Wu et al. 2015b). non-stoichiometric magnetite nanoparticle capped by poly For biomedical applications and in vivo studies, low tox- glucose sorbitol carboxymethyl ether. Recently many imag- icity, biocompatibility, biodegradability, long retention time, ing and therapeutic applications have been performed using and magnetism to localize the IONPs at the target play a ferumoxytol and the results suggest that it can be used in crucial role (Wu et al. 2015b). In diagnosis IONPs, acts as a MR imaging with IONP cell labels for in vivo tracking of probe in magnetic resonance imaging (MRI), Positron emis- stem cells and also can be applied for non-invasive moni- sion tomography (PET), near-infrared fluorescence (NIRF) toring of stem cell therapies in pre-clinical and clinical set- imaging (Ju et al. 2017; Xie et al. 2010) and in biosensors ting (Castaneda et al. 2011). Moreover, studies delineated for detection of biomolecules like glucose, proteins, urea, and uric acid (Chen et al. 2012; Wu et al. 2015a; Yu et al. 2009). Comparatively, IONPs gained attention in therapeutic nanomedicine ranging from cancer treatment to antimicro- bial activity (Nehra et al. 2018; Patra et al. 2017). In thera- nostics, IONPs are applied as nano-carriers, for enhancing the drug activity in combination therapy (IONPs and chem- otherapeutic drugs) or as hyperthermia agents (Ren et al. 2012). Therefore, in the present review article, we focused on the IONPs applications in the domains of diagnosis and therapeutics. IONPs as imaging probe Role of iron oxide nanoparticles as contrast agent in Magnetic Resonance Imaging MRI utilizes gradients of magnetic fields, radio waves and electric fields to elucidate the detailed internal structures of the body. MRI has a wide range of applications in detect- ing diseases or disorders of brain, heart, liver, blood ves- sels, and other vital organs. Recent research advancements have produced several excellent magnetic contrast agents Fig. 1 Schematic illustration of the multifunctional HSA-IONPs for triple active MRI/PET/NIRF imaging. The pyrolysis-derived IONPs such as gadolinium, superparamagnetic iron oxides, ultra- were incubated with dopamine, after which the particles became small (5–10 nm) superparamagnetic iron oxides, gadolinium moderately hydrophilic and could be doped into HSA matrices in a doped carbon nanotubes, quantum dots embedded paramag- way similar to drug loading. Reprinted with permission from ref (Xie netic micelles and soft nanoparticles such as liposomes, et al. 2010) Copyright (2010) Elsevier 1 3 3 Biotech (2018) 8:279 Page 3 of 23 279 ferumoxytol-enhanced MRI was more sensitive for detection based dual imaging modality. The significance of the com- of early necrosis in tumor cells compared to other contrast plex system lies in having optical properties of gold NPs and agents (Aghighi et al. 2015). Reports also revealed that feru- a high dielectric constant of silica NPs ensuring strong light moxytol gained interest to be used in renal failure patients absorption capability (Fig. 2). Hence, they were utilized as a as an alternative to gadolinium-based contrast agents for bimodal MRI-photoacoustic imaging (PAI) agent for imag- vascular MRI (Hope et al. 2015). Furthermore, as the fer- ing and detection of ovarian cancer (Monaco et al. 2017). aheme is taken up by macrophages in liver, lymph nodes Malignant cells are characterized to have a significantly and spleen they can be explored for imaging macrophages, high rate of metabolism and glucose uptake. Utilizing tumors, vascular lesions and other organs (Bashir et al. 2015; this mechanism, cancer tissues are visualized under PET, Vasanawala et al. 2016). involving high uptake of a radiolabelled glucose analog, IONPs are a versatile class of material, which can be [18F]-2-fluoro-2-deoxy- d -glucose (Lindholm et al. 1993). tuned to exhibit multifunctional applications. In one such It is reported that the glucose transporter (Glut) proteins attempt, Xie et al. (Xie et al. 2010) have developed dopamine are found in the plasma membrane of mammalian cells, modified IONPs, which was then encapsulated into human which facilitates the transport of glucose in the cytoplasm. serum albumin (HSA) matrices. It was also shown that the Although there are several Glut proteins, however, Glut-1 HSA coated IONPs can also be labeled with two different has been shown to be involved in the high transportation dyes, Cu-DOTA and Cy5.5, to impart multiplexed imag- of glucose in cancer cells (Singh 2017). Therefore, Glut ing capability and tested them in a subcutaneous U87MG proteins are considered as one of the suitable markers to xenograft mouse model. Results revealed that a tri-modality selectively identify the cancer cells/tissues. The conjugation imaging (including MRI, PET, and NIRF) was very much of Glut antibody with IONPs was shown to diagnose heman- possible under ex vivo and in vivo experimental condition. gioma (a condition in which noncancerous growths of blood HSA coating manifested longer blood circulation time, high vessels occur) through their MRI contrast imaging modality. extravasation and accumulation in targeted tissues and low The study was focussed on the differentiation of infantile uptake in macrophages in the nearby area of tumor. hemangioma from vascular malformation, as Glut-1 is only In the current context, image-guided photothermal ther- expressed in cells of infant hemangioma (Sohn et al. 2015). apy (PTT) is being looked as a promising alternative thera- In general, IONPs acts as a probe for negative contrast peutic modality to the most of the conventional methods. (T contrast agents) due to their superparamagnetic behav- PTT is also expected to have potential to offer a better preci- iour and large magnetic moment. However, a typical dark sion therapy alternative. Owing to the recent developments signal produced in the T image can cause difficulty in in material science, it is possible to synthesize the materi- distinguishing the areas of interest with calcium deposits, als of our interest with variable size, shape, and composi- bleeding and glioma imaging. To overcome the limitation, tion. However, producing multicomponent materials with Juan et al. synthesized citrate coated IONPs (C-ESION) desired dimensions and stability still remains a challenge. with excellent positive (T imaging) and negative contrast Considering this, Ju et al. have developed a monodispersed composite material (Au–Fe C Janus NPs) and used them as multifunctional cancer theranostics. These 12 nm particles exhibited a broad absorbance pattern under near infrared region, which lead to the generation of significant pho- tothermal effect when irradiated with 808 nm laser light. This nanocomposite offered excellent optical and magnetic properties, which was found to be a promising method for triple-modal MRI/multispectral photoacoustic tomography (MSOT)/CT imaging both in in vitro and in vivo experimen- tal models. Authors also modified this magnetic nanocom- posite with HER2 affibody, which showed higher accumula- tion and deep tissue penetration in tumors than unconjugated particles (Ju et al. 2017). In another study by Monaco et al. developed a multi-layered nano-system composed of Fe O 3 4 NPs, coated with inner silica and outer Au layers. These Fig. 2 Fe O NPs coated with inner silica and outer gold layers have 3 4 been entrapped in polymeric micelles, decorated with folic acid moi- NPs were entrapped into polymeric micelles and surface was eties, and tested in vivo for photoacoustic and magnetic resonance conjugated with folic acid to offer them water solubility and imaging detection of ovarian cancer. Reprinted with permission from target recognition. This novel nano-system was shown appli- ref (Monaco et al. 2017) Copyright (2017) American Chemical Soci- cations in targeting and magnetic resonance–photoacoustic ety 1 3 279 Page 4 of 23 3 Biotech (2018) 8:279 through modulating the composition and coating thickness. gold-coated Iron oxide glyco NPs and showed they can be In addition, authors demonstrated that the coating chemistry effectively used for multimodal imaging in CT, MRI, and on NPs surface can change their relaxometric properties, ultrasound (US) as contrast agents. Results explained that the which can be manipulated to generate particles with dif- increased gold coating on NPs surface was able to enhance ferent contrasts. Results explained C-ESION120 displayed the CT contrast through X-ray attenuation. Moreover, NPs T weighed contrast and C-ESION140 showed T contrast with reduced size, sugar coating and negative surface charge 1 2 signal characteristics. Hence, the modified coating enabled allowed for long circulation time in blood and proved to the maghemite NPs for T high-resolution MR angiography be biocompatible (Mónica Carril 2014). Additionally, Naha and also provided standard T contrast to utilizing them for et al. reported the synthesis of a composite consisting of bis- a full range of applications in MRI (Pellico et al. 2017). muth–iron oxide nanoparticles (BION) with dextran coating. Further, Ning et al. synthesized Gd-doped and PEG-coated Data revealed that no cytotoxicity was observed in HepG2 IONPs (PEG-GdIO) having T –T bimodal contrast ability (human liver cancer cell line) and BJ5ta (human fibroblast 1 2 and demonstrated the simultaneous T –T contrast imaging cell line) after 24 h incubation with NPs. In vivo CT imag- 1 2 in mice bearing glioma. Results revealed that after 1 h of ing with optimized NPs concentration showed the contrast NPs injection T and T weighted images showed brighter in heart and blood vessels indicating prolonged circulation 1 2 and darker contrast compared to pre-injection MR images. half-life. Further, some contrast was observed in liver and Moreover, the contrast enhancement was analyzed by con- spleen suggesting that the non-specific nanoparticle accumu- trast to noise ratio and significant improvement in signals lation in these organs. It was concluded that NPs are biocom- was found for both T and T contrast images. Hence, it was patible, biodegradable and possess strong X-ray attenuation 1 2 concluded that PEG-GdIO NPs can be used as dual con- characteristics, which can be used as a strong contrast agent trast agent for brain glioma detection (Xiao et al. 2014). for dual CT and MRI imaging (Naha et al. 2014). In another Cha et al. modified Fe O NPs (Fe O @GCP—Fe O sur- attempt, Perlman et al. indicated that IONPs can be used in 3 4 3 4 3 4 face modified with glutathione, cyclodextrin and polymer) ultrasonic computed tomography (UCT) for breast imaging. through polymer coating composed of β-cyclodextrin core The imaging showed an improvement in contrast to noise and poly [2-(dimethylamino) ethyl methacrylate] arms and ratio and can also serve as a pre-screening platform for dis- in association with reduced glutathione (GSH) as a model ease diagnosis. Moreover, it was suggested that these NPs drug. The designed platform was expected for simultane- can be applied for multimodal MRI-ultrasound imaging pur- ous diagnosis and treatment purposes. Authors suggested poses (Perlman and Azhari 2017). Reguera et al. designed a Fe O NPs coated with these star polymers exhibited more novel gold–iron oxide-based Janus magnetic-plasmonic NPs 3 4 GSH association compared to linear polymers and showed as contrast agents for imaging under CT, MRI, PAI, TEM, better stability in serum solutions. Further Fe O @GCP surface enhanced Raman spectroscopy (SERS) and optical 3 4 rendered low cytotoxicity and possessed enhanced T MRI microscopy. These complementary techniques allow obtain- characteristics. Results showed significant bright enhance- ing maximum information and can serve as a multipurpose ment observed for T weighted images of liver visualization biomedical platform (Reguera et al. 2017). suggesting that the modified NPs can be used for diagnosis and treatment of chronic liver diseases (Cha et al. 2017). Iron oxide nanoparticles in positron emission tomographic imaging Use of iron oxide nanoparticles as contrast agent in computed tomography PET is a nuclear imaging method that provides whole-body imaging and evaluates tissue and organ functions thus ena- CT is an X-ray based whole body imaging technique that bles quantification and localization of activity. However, it combines series of computer processed X-ray images to cannot reveal anatomical or morphological imaging. So to construct the cross-sectional images of specific areas. CT achieve advancements in imaging, CT, MRI or US can be is used to diagnose diseases or internal injuries in blood combined to form a hybrid system such as PET/CT or PET/ vessels, bones, soft tissues and other parts of the body. Clini- MRI for better resolution and anatomy of cells and tissues cally approved CT contrast agents for intravenous injection (Evertsson et al. 2017). de Rosales et al. reported the synthe- are iodinated small molecules or barium suspensions. Due sis of a novel NPs system through bifunctional chelator dithi- to hypersensitive to iodinated contrast and renal impaired ocarbamate–bisphosphonate conjugation to Cu and dextran patients there is a need for better contrast agents. So, several coated IONPs for PET and MR imaging. Further, the labe- nanoparticles including metallic, polymeric, liposomes, lipo- ling of clinically available IONPs (Endorem/Feridex) with proteins, micelles, and emulsions have been reported to yield Cu-based bifunctional chelator was performed and their better results as contrast agents for CT imaging (Cormode dual-modality imaging was demonstrated in vivo in lymph et al. 2014; Thomas et al. 2013) Carril et al. worked on 6 nm nodes (Torres Martin de Rosales et al. 2011). Nahrendorf et 1 3 3 Biotech (2018) 8:279 Page 5 of 23 279 al. conjugated a PET tracer Cu to dextran coated magneto for the construction of non-enzymatic biosensors to test the fluorescent NPs to yield a tri-modality reporter ( Cu-TNP) levels/concentrations of glucose, glutathione, cholesterol, for PET, MRI and fluorescence imaging. The capability of H O , urea, creatinine and biomarkers for cancer diagno- 2 2 multimodal NPs was applied to detect macrophages in ath- sis (Gawande et al. 2016; Lin et al. 2014a, b; Mahato et al. erosclerotic plaques. Authors hypothesized that the in vivo 2018a, b; Vallabani et al. 2017; Wang et al. 2017; Zheng PET signal correlates well with the inflammatory plaques et al. 2011). These biomolecules are well-known biomark- observed by MRI, u fl orescence imaging and o fl w cytometry ers for several diseases, thus the developed biosensors (Nahrendorf et al. 2008). Xiaoqiang et al. developed a mul- could be used for the early diagnosis of these diseases. In tifunctional nanocarrier functionalized with tumor targeting general, the peroxidase-like activity of these nanozymes is ligand, DOX- observed at an optimum pH of 3–5, through the generation conjugated and Cu labeled IONPs. The carrier pro- of hydroxyl radicals by Fenton reaction. For glucose detec- vides targeted anticancer drug delivery and PET/MRI-based tion, most of the colorimetric assays follow a two-step pro- dual imaging modality of tumors expressing integrin α β . cedure. In the first step, glucose gets oxidized in presence v 3 In vitro studies explained cRGD ligand (cyclic arginine- of glucose oxidase (GOx) to release H O at neutral pH. 2 2 glycine-aspartic peptides) conjugated NPs exhibited more In the second step, the obtained H O along with HRP or 2 2 cellular uptake and tumor accumulation compared to free peroxidase mimetics are allowed to oxidize the substrates NPs shown by quantitative PET imaging and biodistribution like 3,3′,5,5′-tetramethylbenzidine (TMB), 2,2′-azino-bis(3- analysis (Yang et al. 2011). A similar study was performed ethylbenzothiazoline-6-sulphonic acid) (ABTS) and O-phe- by Lee et al. to develop a bifunctional probe for PET and MR nylenediamine (OPD) to form the colorimetric product at imaging. Polyaspartic acid coated IONPs were synthesized acidic pH. Although nanozymes degrade H O rapidly and 2 2 and conjugated with a cRGD ligand for integrin targeting follow the oxidation of the products by hydroxyl radicals, and labeled with CuDOTA for PET analysis (Lee et al. still the reaction suffers from several shortcomings such as 2008). Additionally, Chakravarty et al. synthesized Ge- lower substrate affinity and specificity than natural enzymes. labeled metal oxides by mixing IONPs with Ge ions. The Such events lead to the lower performance of nanozymes, simple method has an advantage in forming intrinsic radiola- which ultimately faces limited applicability in sensing and belled NPs without any use of chelators. In addition, these biomedicine. Therefore, it becomes necessary to develop NPs can be used for simultaneous PET and MRI imaging novel ways to enhance the catalytic activity of nanozymes. (Chakravarty et al. 2014) (Table 1). To address this issue, Yu et al. have studied the impact of citrate, glycine, polylysine, dextran and heparin coating on the peroxidase mimetic MNPs (Yu et al. 2009). They Bio‑sensing applications of iron oxide observed that the developed anionic NPs had high affinity nanoparticles towards TMB, whereas cationic NPs showed high affinity for ABTS. Based on the substrate affinity, they were able to Role of Iron oxide nanoparticles as nanozymes detect glucose in the traditional two-step process and sug- gested that the nanozymatic activity can also be extended Recent developments in nanotechnology have also aimed to other biomedical applications. Bhagat et al. have devel- towards the construction of novel enzyme mimetics oped Gold-core/Cerium oxide-shell NPs exhibiting a mul- (nanozymes) exhibiting biological oxidase, peroxidase, tienzyme complex-like activity including catalase, SOD, catalase, and superoxide dismutase-like activities (Gao et al. and peroxidase enzyme-like activities. Kinetic parameter 2017; Karim et al. 2018; Lin et al. 2014d; Shah and Singh study related to peroxidase activity demonstrated that the 2018). Nanozymes are nanomaterials possessing intrin- core–shell nanozyme activity was comparable to the natural sic biological enzyme-like properties, which offer several enzyme, horseradish peroxidase (HRP). In addition, authors advantages over natural enzymes such as high stability also explained that oxidation of TMB was carried through and activity at varying conditions of pH and temperatures, electron transfer instead of hydroxyl radical participation. cost effectivity, easy manipulation and multiple applica- Additionally, the enzyme activity was conserved at a broad tions on a single platform. The shape, size, and composi- range of pH (2–11) and temperatures (up to 90 °C). How- tion controlled synthesis of nanomaterials provides easy ever, the nanozyme exhibited optimum SOD and catalase modulation of their nanozymatic activity, which is one the activity at neutral pH and for peroxidase, it was found at major limitations with natural enzymes. Various metal and acidic pH. Finally, the nanozymatic (peroxidase mimetic) metal oxide-based nanomaterials such as IONPs, Gold, Sil- activity was utilized for the detection of glucose in a range ver, Copper, and nanosheets of graphene, MoS , WS are from 100 µM to 1 mM in a time span of 5 min and at pH 2 2 shown to display horseradish peroxidase (HRP)-like activ- 4 (Bhagat et al. 2017). Additionally, Wu et al. developed a ity. These enzyme-mimetic activities are shown to be used magnetic core–shell microgel system with immobilized GOx 1 3 279 Page 6 of 23 3 Biotech (2018) 8:279 1 3 Table 1 Role of iron oxide nanoparticles in various imaging modalities Nanoparticle/material Size (nm) Applications/results References Ferumoxytol (Feraheme) 17–30 Treatment for anemia in renal failure patients Aghighi et al. (2015), Bashir et al. (2015), Castaneda Used in MR imaging for Stem cell tracking and mac- et al. (2011), Hope et al. (2015) and Vasanawala et al. rophages. Showed high T signal near tumor necrosis (2016) regions (can be used for early necrosis detection). Can be effectively used for MR angiography in renal failure patients compared to gadolinium-based contrast agents IONPs coated with HSA, Dopamine and labeled with Cu- 15 Used for in vivo tri-modality imaging where MRI used Xie et al. (2010) DOTA and Cy5.5 for the study of particle distribution pattern. Under PET imaging showed better signal to noise ratio. NIRF used for both in vivo and ex vivo fluorescence-based imaging Fluorescent MNPs 10–40 Used for cell imaging (biological imaging) García et al. (2018) JNPs (Au-Fe C Janus nanoparticles) 12 Applied for triple-modal imaging (in vivo and in vitro) Ju et al. (2017) Including MRI, CT, and PAI. Results showed that targeting of NPs was achieved by affibody conjugation (Au-Fe2C- Z ) HER2:342 Lipophilic Core − Shell Fe O @SiO@Au (Fe O coated 157–222 Results showed targeting of cancer cells through folate Monaco et al. (2017) 3 4 2 3 4 with inner silica and Au outer layer) receptors. Dual imaging capability for detection of ovar- ian cancer using MRI, and PAI GLUT1-Fe O NPs (Glucose transporter antibody conju- 10 Differentiation of infantile hemangioma from vascular Sohn et al. (2015) 3 4 gated Fe O NPs) hemangioma through MRI imaging was realized 3 4 C-ESION (Citrate coated IONPs) 3.5–4.5 For both T and T contrast imaging, where C-ESION120 Pellico et al. (2017) 1 2 used for T -weighted angiography and C-ESION140 for T -weighted MRI imaging PEG-GdIO (PEGylated Gd-doped iron oxide NPs) 4.29–4.74 Showed simultaneous T –T dual-modal MRI imaging and Xiao et al. (2014) 1 2 efficient diagnosis of brain gliomas Fe O @GCP 10–22 Suitable for T MRI contrast where T weighted images of Cha et al. (2017) 3 4 1 1 mice liver were capture with a signal intensity of ~ 1.2 times more compared to control Ultra-small IONPs 3–4For T contrast imaging using MRI Bao et al. (2018) Fe O @Au@Glc/CO H NPs (Gold-Coated Iron Oxide 6.1 Can be used as multimodal contrast agent for CT, T Mónica Carril (2014) 3 4 2 2 Glyco-nanoparticles) weighted MRI and US imaging BION (Dextran coated bismuth–iron oxide nanohybrid) 5–15 Biocompatible and biodegradable NPs used for CT and T Naha et al. (2014) weighted MRI imaging Fe O 10 Used for ultrasonic breast imaging, also be applicable for Perlman and Azhari (2017) 3 4 multimodal MRI-ultrasound imaging Gold-iron oxide NPs 20–50 Showed potential for multi-purpose imaging such as con- Reguera et al. (2017) trast agent for CT, T weighted MRI imaging and PAI 64 64 Cu-IONPs ( Cu and dextran coated IONPs) 5 Showed better contrast for in vivo PET-MR imaging Torres Martin de Rosales et al. (2011) Cu-TNP (IONPs as trireporter NPs) 20 Used for tri-modality NPs system (PET, MRI and fluores- Nahrendorf et al. (2008) cence imaging) for direct detection of macrophages in inflammatory atherosclerosis 3 Biotech (2018) 8:279 Page 7 of 23 279 and HRP molecules. Due to co-entrapment of enzymes, they utilized the magnetic microgel for the colorimetric detection of glucose in a single step at pH 5.5 (Fig. 3). Moreover, they suggested that this detection system can also be extended for detecting biomolecules through new oxidase or peroxidase platforms (Wu et al. 2015a). Composite materials have also been studied for the pos- sible nanozymatic activities. In one such attempt, carbon nanotube/polyaniline-based metal oxide (Fe‚ Co‚ Ni) NPs are synthesized to show peroxidase mimetic activity using TMB and phenol/4-aminoantipyrine (4-AAP/phenol) to study the peroxidase-like activity and translated into a col- orimetric method for glucose detection (Navvabeh Salariza- deh et al. 2017). Additionally, Vazquez-Gonzalez et al., have shown that NPs composed of the Prussian blue (PB), CuFe, FeCoFe, and FeCo inorganic clusters mimic the peroxidase activity. They suggested that PBNPs catalyze the oxidation of NADH by H O to form NAD which can be applied for 2 2 chemical transformations by N AD dependent enzymes such as ethanol dehydrogenase (Fig. 4). It was also found that the FeCo NPs catalyzed chemiluminescence generation in presence of H O and luminol and extended this system for 2 2 effective sensing of glucose (Vazquez-Gonzalez et al. 2017). Recently, bimetallic 2D nanosheets are also reported to act as biological peroxidase enzyme. In this context, Tan et al. synthesized bimetallic nanosheets exhibiting peroxidase-like activity, which can be modulated with the single-stranded DNA (ssDNA). The major attraction of this method was the switchability of peroxidase-like catalytic activity with DNA (Fig. 5). By modulating the enzyme-like activity of these nanosheets they achieved an ultra-sensitive detection of H O with a range of 2.86–71.43 nM and comparable 2 2 detection of glucose with a linear range of 12.86–257.14 µM (Tan et al. 2017). Iron oxide nanoparticles in electrochemical sensing and role of biomolecules in enhancing nanozyme activity Unlike enzymatic reactions, nanomaterials exhibit the non- enzymatic way to detect the biomolecules. Since these methods are not constrained by the need of special condi- tions of pH and temperature, the process of detection does not get interference with other comparative biomolecules. Baby and Ramaprabhu et al. reported a superparamagnetic nanocomposite composed of SiO coated Fe O NPs dis- 2 3 4 persed on multiwalled-carbon nano tubes (Fe O @SiO / 3 4 2 MWNT) exhibiting enhanced electron transfer ability and biocompatibility. This system was successfully applied to the development of a glucose and cholesterol sensor with- out any interference from other biomolecules and did not involve any enzyme (Baby and Ramaprabhu 2011). Further, Nor et al. developed a high sensitive biosensor for glucose 1 3 Table 1 (continued) Nanoparticle/material Size (nm) Applications/results References cRGD-conjugated SPIO nanocarriers (cRGD-functional- 10 Multifunctional NPs for tumor targeting through conjugated Yang et al. (2011) and Lee et al. (2008) ized, DOX-conjugated, and Cu-labeled superparamag- cRGD (tumor targeting ligand) and quantitative PET-MRI netic iron oxide nanoparticles) imaging Germanium-69-Labeled IONPs 10 Used for in vivo dual modality PET and MRI imaging Chakravarty et al. (2014) 279 Page 8 of 23 3 Biotech (2018) 8:279 Fig. 3 Synthesised magnetic core–shell microgels for single step colorimetric detection of glucose. Reprinted with permis- sion from ref (Wu et al. 2015a) Copyright (2015) Royal Society of Chemistry Fig. 5 Schematic illustration of peroxidase-like activity and its con- trollability regulated by DNA of Cu(HBTC)–1/Fe3O4–AuNPs Fig. 4 Prussian blue (PB), and the cyanometalate structural analogs, nanosheets. Reprinted with permission from ref (Tan et al. 2017) CuFe, FeCoFe, and FeCo, are examined as inorganic clusters that Copyright (2017) Royal Society of Chemistry mimic the functions of peroxidases. Schematic showing PB NPs cata- lyzed oxidation of NADH by H O to form N AD and chemilumines- 2 2 cence generation by the FeCo NPs catalyzed oxidation of luminol by Composites of multiwalled-carbon nanotubes doped H O . Reprinted with permission from ref (Vazquez-Gonzalez et al. 2 2 metal oxide NPs (NiO, ZnO, and Fe O ) are coated on glassy 3 4 2017) Copyright (2017) American Chemical Society carbon electrode and used for the sensitive detection of sero- tonin from body fluids such as urine. Serotonin is a well- detection using Nafion/GOx/IONPs/screen printed carbon known neurotransmitter and neuromodulator which plays electrode (SPCE). The amperometric biosensor exhibited a a significant role in several biological processes like liver wide range of glucose detection with a lower limit of 7 µM degeneration, endocrine regulation, anxiety, and depression. (Nor et al. 2017) (Fig. 6). In the similar concept, Kacar et Hence, the determination of serotonin levels in the blood al. developed an amperometric biosensor for creatine moni- can assist to diagnose several diseases. Using this mate- toring using F e O -nanoparticles-modified carbon paste rial, authors showed the voltammetry-based determination 3 4 electrodes. The method relies on two enzymatic catalyzed of serotonin, dopamine and ascorbic acid, simultaneously reactions, creatinase, and sarcosine oxidase to generate H O with high signal to noise ratio (Fayemi et al. 2017). Urea 2 2 and finally, the sensor sensitivity depends on the response is another marker for kidney failure, obstructions in uri- towards H O for creatine determination (Kacar et al. 2013). nary tract, liver failure and other gastrointestinal problems. 2 2 Since the creatine level in the human blood and urine acts as Ali et al. devised a potentiometric sensor by immobilizing a clinical parameter to monitor muscle damage, this system urease enzyme over chitosan conjugated F e O NPs for 3 4 could be of immense benefit to clinical monitoring of these detecting urea in the range of 0.1–80 mM (Ali et al. 2013). biomolecules. Andrea et al. developed IONPs for the sensitive and direct 1 3 3 Biotech (2018) 8:279 Page 9 of 23 279 Fig. 6 Schematic illustration of Nafion/GOx/IONPs/SPCE biosensor for electrochemical based detection of glucose. Reprinted with permission from ref (Nor et al. 2017) Copyright (2017) Elsevier detection of biomolecules from biological samples. The showed that with the use of ATP, IONPs exhibited excellent NPs were functionalized with lipopolysaccharides obtained peroxidase mimetic activity at physiological pH. Moreover, from a Brucella species and detected the presence of Bru- the enzymatic activity was preserved over a wide range of cella antibodies in serum. Further authors suggested that pH and temperatures in presence of ATP. They utilized the the method is versatile and NPs can be functionalized with property for single step detection of glucose at pH 7.4 and different antigens on the surface, which could be used for further extended to detect glucose level in human blood easy identification of a variety of analytes from the body serum (Vallabani et al. 2017). Further to this study, Liang fluids (Fornara et al. 2008). et al. synthesized novel NPs by growing coordinate poly- 3+ To increase the efficiency of nanozymes and overcome mer (CP) shell made of Fe and Adenosine monophosphate the pH constraints, synergistic molecules like nucleobases, (AMP) on F e O NPs. CP shell showed an advantage in 3 4 nucleosides, nucleotides, and DNA are supplemented in the encapsulating a wide variety of guest molecules like nucleic solution or coated on to the surface of NPs. This synergistic acids, proteins, fluorophores, and NPs. Authors explained effect allows the design of simple and novel sensors for bio- that the shell has enhanced peroxidase-like activity due molecule detection at the desired pH (Lin et al. 2014c; Pu to Fe O present in the core and applied this peroxidase 3 4 et al. 2017; Shah et al. 2015). Thus, to enhance the utility nanozyme for glucose bio-sensing. GOx was entrapped in and translate the system into a point-of-care device platform, the shell of Fe O NPs for glucose detection and monitored 3 4 one-step method of detection is imperative. In this context, with a sensitivity of 1.4 µM (Liang et al. 2016). Additionally, Vallabani et al. reported a novel strategy to overcome the Yang et al. reported that adenosine analogs with phosphate limitation of acidic pH for hydroxyl radical generation and groups can enhance the peroxidase-like activity of F e O 3 4 1 3 279 Page 10 of 23 3 Biotech (2018) 8:279 NPs. The improved activity was detected through the oxida- Iron oxide nanoparticles in hyperthermia tion reaction of H O and amplex ultra-red reagent gener- and photo thermal therapy 2 2 ating fluorescence. Here the enhanced peroxidase activity of adenosine phosphate analogs showed the activity trend Hyperthermia is a thermal therapy to produce heat near a as AMP > ADP > ATP. Based on the protein adsorption on local or a systemic tumor by energy sources like micro- NPs authors also developed a turn-off system for detection waves, radio waves, ultrasound energy and magnetism. of urinary proteins (Yang et al. 2017) (Table 2). Recently, it has been realized that the conventional meth- ods of cancer treatment suffer from several limitations such as side effects, drug resistance, low availability of drug at the site of action, fast renal clearance, etc. These challenges have allowed researchers to combine the chemotherapy and radiotherapy with hyperthermia. In magnetic hyperthermia, Table 2 Summary of bio-sensing applications shown by iron oxide nanoparticles Nanoparticle/material Size (nm) Applications/results References Microgel embedded IONP-GOx-HRP ~ 200 Exhibited peroxidase like activity. Colorimetric Wu et al. (2015a) detection of glucose was carried in a single step at pH 5.5 Prussian blue FeCo NPs 40–50 PBNPs catalyzed the oxidation of NADH by Vazquez-Gonzalez et al. (2017) H O to form N AD (showed dehydrogenase 2 2 like activity). FeCo NPs catalyzed chemilu- minescence generation in presence of H O 2 2 and luminol (showed Peroxidase like activity). Glucose detection was performed using FeCo NPs Cu(HBTC)-1/Fe O -AuNPs nanosheets with 5.99 ± 2.58 Enhanced TMB oxidation was observed in pres- Tan et al. (2017) 3 4 ssDNA ence of single stranded DNA. 2D bimetallic immobilized MOF nanosheets were applied for detection of H O (2.86–71.43 nM range) 2 2 and glucose (12.86 to 257.14 µM range) Fe O @SiO/MWNT (SiO coated Fe O NPs 5–15 Biosensor was applied for detection of glu- Ramaprabhu (2011) 3 4 2 2 3 4 dispersed on Multiwalled-carbon nano tubes) cose (3 µM–14 mM range) and cholesterol (10 µM–4 mM range) FeNPs@Co O (IONPs loaded in Co O hollow 900 Applied for glucose detection with a linear Zhao (2018) 3 4 3 4 nanocages) range of 0.5–30 µM (limit of detection was 0.05 µM) Fe O -nanoparticles-modified carbon paste – Creatinine was determined with a detection Kacar et al. (2013) 3 4 −7 −1 electrodes limit of 2.0 × 10 mol L Graphene oxide/Fe O nanocomposite 50 Biosensor for determination of glucose, with a Wang (2018) 3 4 range of 0.5–10 mM MWCNT doped with Ni, Zn, Fe 10–50 Serotonin was determined with a detection limit Fayemi et al. (2017) −3 of 5.98 × 10 µM–62.8 µM Chitosan-IONPs with urease – Applicable for the detection of urea Ali (2013) IONPs 19.5 Brucella antibodies detection with a detection Fornara et al. (2008) −1 limit of 0.05 µg mL Fe O NPs 13 ± 3.5 ATP-mediated peroxidase like activity of Fe O Vallabani et al. (2017) 3 4 3 4 NPs was observed at pH 7.4. Glucose detec- tion was carried in a single step at physiologi- cal pH with a colorimetric detection limit of 50 µM 3+ Fe O NPs with Fe AMP shell 10–20 Glucose detection was demonstrated with a Liang et al. (2016) 3 4 detection limit of 1.4 µM Fe O NPs ~ 13 Exhibited peroxidase like activity. Can be Yang et al. (2017) 3 4 applicable as a fluorescent turn-off system for urinary protein detection 1 3 3 Biotech (2018) 8:279 Page 11 of 23 279 the intratumorally injected IONPs generate heating effect graphene NPs (Boca et al. 2011; He et al. 2014; Liu et al. after exposing to an external magnetic field and induce the 2007; Yavuz et al. 2009). Other morphologies of IONPs are cell death near the tumor zone (Elham Cheraghipour 2012; also developed for the photothermal treatment of diseases. Kolosnjaj-Tabi and Wilhelm 2017). Due to poor cellular Espinosa et al. have used nanocubes of IONPs and showed architecture, cancer cells are very prone to be damaged by that when these nanocubes are exposed to the magnetic field the slight increase in the surrounding temperature. Addi- as well as near-infrared laser irradiation, two- to five fold tionally, using hyperthermia strategy, the temperature of the amplification in the production of heat was generated than surrounding environment can be increased up to 55–60 °C, when used magnetic field alone (Fig. 7). Moreover, it was which can be very well withstood by normal healthy cells, demonstrated the dual-mode stimulation generated efficient but not by cancerous cells. Moreover, IONPs can be used to heat with low iron concentration (0.25 M) and acceptable prepare synergistic nano-hybrids tuned for magnetic hyper- laser power irradiation (0.3 W/cm ) and resulted in a com- thermia and photothermia. Photothermal therapy is also pos- plete cell death and solid tumor suppression (Espinosa et al. sible with the use of other nanoparticles such as anisotropic 2016). In another attempt, Niu et al. developed a nanosys- nanostructures of gold, copper, silver, carbon nanotubes, and tem comprising of IONPs (Fe O ), indocyanine green (ICG) 3 4 and perfluoropentane (PFP) encapsulated in poly (lactideco- glycolide) (PLGA) nanoparticles for NIR induced PTT. The experiments with MCF-7 tumors in mice showed that these multifunctional NPs can enhance tumor ablation upon NIR laser irradiation and can act as a key photothermal agent against the tumors (Niu et al. 2017). Addressing hyperthermia, Mazario et al. synthesized 10 nm sized MNPs functionalized with HAS protein and the experimental data revealed these functional materials have the potential role in mediating magnetic hyperthermia by enhancing the temperature of cancer cells. Moreover, authors suggested that heating could induce irreversible damage to cellular proteins and enzymes and thereby the regulation of apoptosis in cells and tissues (Mazario 2017). In a related study, Shen et al. synthesized a magnetic nanocluster for PTT using near-infrared light irradiation. They found that after radiation exposure clusters of Fe O produced more 3 4 heating thereby impart significant cytotoxic to A549 cells (human lung carcinoma) compared to bigger sized F e O 3 4 NPs. The mechanistic studies revealed the cell death was caused due to apoptosis, but not necrosis. Further, in vivo studies demonstrated that these clusters can be applied for Fig. 7 Dual mode magneto-photo-thermal approach using iron oxide promising tumor treatment through PTT (Fig. 8) (Shen et al. nanocubes for tumor ablation. Reprinted with permission from ref (Espinosa et al. 2016) Copyright (2016) American Chemical Society 2015). Chen et al. have developed highly crystalline IONPs Fig. 8 Infrared thermal images of phosphate buffered saline (PBS), individual and clustered magnetic Fe O NPs with the 3 4 concentration of 100 µg/mL injected in A549 tumor sample under NIR laser irradiation for 0–180 s. Reprinted with permis- sion from ref (Shen et al. 2015) Copyright (2015) Elsevier 1 3 279 Page 12 of 23 3 Biotech (2018) 8:279 Table 3 Summary of iron oxide based nanoparticles for hyperthermia and photo thermal therapy Nanoparticle/material Size (nm) Applications/results References IONPs (nano-cubes) 20 The dual mode (hyperthermia and PTT) of Espinosa et al. (2016) treatment amplified the heating effect by two- to fivefold in comparison with magnetic stimulation alone. Results showed that in both in vitro (SKOV3) (ovarian cancer), PC3 (prostate cancer) and A431 (epidermoid can- cer) and in vivo (A431 cancerous cells were injected in nude NMRI mice) complete cell death was observed after dual mode exposure ICG/Fe O loaded PLGA NPs Fe O : 10 Used as an efficient treatment by PTT. In vitro Niu et al. (2017) 3 4 3 4 Total shell: ~300 treatment of NPs to MCF-7 breast cancer cells confirmed the damage to cells and in vivo studies demonstrated IONPs can be used as an effective agent for tumor ablation Carboxyl-amine functionalized SPIONs based ~ 20 In vitro hyperthermia studies revealed tereph- Kandasamy (2018a) ferrofluids thalic acid (TA) and aminoterephthalic acid (ATA) coated SPIONs induced ~ 90% cell death in breast cancer cells (MCF-7) IONPs with HSA 10 Used for thermal therapy. MNPs exhibited a Mazario (2017) −1 saturation magnetization of 63 emu g at 310 K and produced a localized heat in pres- ence of an alternating magnetic field Clustered magnetic Fe O NPs Fe O : 15 Used for PTT. The clustered NPs induced high Shen et al. (2015) 3 4 3 4 Clustered Fe O : 225 temperature and proved to be more cytotoxic 3 4 against A549 cells both in vitro and in vivo SPIONs 6–10 Hyperthermia based thermotherapy for liver Kandasamy (2018b) cancer treatment Crystallized IONPs (HCIONPs) 15 Showed effective PTT against SUM-159 tumor- Hongwei Chen (2014) bearing mice PEGylated Fe@ F e O (PEGylated iron/iron 13.4 ± 0.8 These multifunctional NPs can be applied for Zhou et al. (2014) 3 4 oxide core/shell NPs) targeting, MRI imaging and PTT Fe O @CMCT (carboxymethyl chitosan stabi- 177 Used for PTT. NPs were found accumulated in Shen et al. (2013) 3 4 lized Fe O NPs) the mice tumor region and PTT induced the 3 4 increase in temperature up to ~ 52 °C (HCIONPs) coated with the anti-biofouling polymer and used then for photothermal cancer therapy. Results revealed NPs were effectively accumulated in the tumor site of SUM- 159 tumor-bearing mouse though permeability and retention effect. Further laser irradiation exhibited complete tumor regression within 3 weeks compared to control. Authors sug- gested that enhanced PTT was due to high crystalline and preferred lattice plane orientations of as prepared HCIONPs compared to normal Fe O NPs (Hongwei Chen 2014). 3 4 Multifunctional IONPs are also designed and have shown better results than their uni-functional counterparts. Fig. 9 Schematic illustration of magnetic targeting, MRI and NIR In this context, PEGylated Fe/Fe O NPs have been devel- photothermal therapy by multifunctional PEGylated Fe/Fe O NPs. 3 4 3 4 Reprinted with permission from ref (Zhou et al. 2014) Copyright oped for exhibiting triple functions comprising PTT, tar- (2014) Elsevier geting, and MRI (Fig. 9). Targeting of cells was achieved with neodymium magnet placed beside a xenograft tumor developed from HeLa cells. The multi-modality allowed the imparts biocompatibility and avoidance to the reticuloen- NPs to accumulate in the tumor region, therefore, exhib- dothelial system (RES), which renders the long-term cir- ited intense MRI signal with high photothermal activity culation in blood plasma (Larson et al. 2012). Therefore, (Zhou et al. 2014). PEG coating on nanoparticle surface biocompatible nanomaterials would be an ideal candidate 1 3 3 Biotech (2018) 8:279 Page 13 of 23 279 for multifunctional applications cell targeting, MRI, sensing, compared to the radiotherapy alone. Mechanistically, they hyperthermia, and PTT. For instance, Shen et al. synthe- found that targeting of breast cancer cell was achieved with sized a carboxymethyl chitosan coated F e O NPs, which deoxy-d -glucose moiety conjugated on IONPs surface and 3 4 exhibited extremely low toxicity and high PTT efficiency. doxorubicin acted as therapeutic agent, thus the combined Furthermore, they stated that these NPs platform can be eas- effect leads to the improved breast cancer radiotherapy by ily fabricated for multiple applications (Shen et al. 2013) increased localization of NPs. When investigated further, (Table 3). it was found that the extent of cytotoxicity in tumor cells was much more, with minimum side effects and damage to normal healthy cells. In another strategy, Ye et al suggested Iron oxide nanoparticles as delivery agentsthat Fe O NPs can increase the efficacy of cryoablation; 3 4 a process uses extreme cold conditions to treat cancerous Drug delivery applications cells. Their data indicated that Fe O NPs altered intracel- 3 4 lular ice formation ability during freezing, recrystallization, Effective treatment of cancer still remains a major challenge and thawing, which leads to the enhanced killing of MCF-7 in medicine due to several problems such as drug/multidrug cells. Therefore, the idea of enhanced ablation using IONPs resistance, lack of selective targets for a tumor (El-Boubbou can be successfully applied to effectively treat tumors in near 2018; Vasir and Labhasetwar 2005). Nanotechnology has future (Ye et al. 2017). recently shown some success in effective cancer treatment Cisplatin is platinum-based anticancer agent reported due to the unusual properties of materials. Among several to treat various types of cancers including lung, testicu- NP types, IONPs have gained the most attention for appli- lar, bladder, ovarian, breast, and brain tumors (Dasari and cations in nanomedicines due to some of the key attributes, Tchounwou 2014). However, the excess usage of cisplatin including stable colloidal suspension, resistance to in vivo is also reported to exhibit various side effects such as kid- degradation, presence of large surface area to graft targeting ney damage, neurotoxicity, bone marrow suppression, heart moieties, high payload delivery of drugs, synergistic activity diseases, and allergic reactions (Barabas et al. 2008). It is in improving the sensitivity of drugs towards cancer treat- also well known that the drug resistance shown by tumor ment, and reversing the resistance of cancerous cells (Bah- cells limits their probability of clinical trial success. To over- rami et al. 2017; Ulbrich et al. 2016). come these limitations, platinum drugs are suggested to be Traditional methods of cancer treatment include surgery, encapsulated into polymers or loaded into multifunctional chemotherapy, radiotherapy, and combinational therapy nanocomposites for effective treatment of cancers. In this to alleviate the tumors. However, damage to surrounding context, Yan Zhang et al. fabricated a nanocomposite com- cells around a tumor and radio-resistance of cells limits prising of Fe O core and polymeric inner shell covered with 3 4 the effectiveness of these conventional therapies. The mul- PEG, and folate groups, and the cisplatin was encapsulated tifunctional nature of IONPs has been recently exploited into the inner shell through coordination of amino groups for the effective drug delivery for cancer and other disease (Yan Zhang 2014). The in vitro release kinetics of cisplatin treatment. Pirayesh Islamian et al. used superparamagnetic showed better release at acidic pH (pH ~ 4.5) and resulted mesoporous hydroxyapatite conjugated doxorubicin and in a cytotoxic response in HeLa cells through ligand-medi- deoxy-D-glucose nanocomposites to boost breast cancer ated targeting of folate receptors (overexpressed on HeLa chemo and radiotherapy (Pirayesh Islamian et al. 2017). cells) (Fig. 10). Additionally, Ebrahimi et al. have devel- They worked on SKBR3 and T47D breast cancer cell cul- oped a PLGA-PEG copolymer system by emulsion method, ture models and reported that the cell viability was sig- which encapsulated Fe O NPs with doxorubicin (DOX) 3 4 nificantly decreased with combined nanocomposite effect drug. With the controlled DOX release in tumor cells, this Fig. 10 Schematic repre- sentation of the structure of FA-CIS-POLYMER-Fe O 3 4 nanoparticles and cisplatin loading and release. Reprinted with permission from ref (Yan Zhang 2014) Copyright (2014) Springer Nature 1 3 279 Page 14 of 23 3 Biotech (2018) 8:279 biodegradable nanocomposite was designed to minimize the produced IONPs laid an efficient combination platform for drug uptake in normal cells and also to control the drug imaging through Fe O contrast (MRI), red fluorescence 3 4 amount and targeting via copolymer coated IONPs and pH. (auto fluorescing DOX) and green fluorescence (fluores- The results revealed that the drug release was high at acidic cein isothiocyanate). Results revealed that significant drug pH and found effective as a chemopreventive and chemo- internalization was obtained in pancreatic cancer cells (MIA therapeutic agent for effective treatment of lung and other PaCa-2 cells). Further, the dual-fluorescent tracking mode solid tumors (Ebrahimi 2014a, b). showed that the DOX was cleaved from the NPs and accu- Epidermal growth factor receptor (EGFR) is also a well- mulated at the targeting site (nucleus). Such strategies could known targeting moiety, which has been well-explored for also be utilized for conjugation of an additional antibody to the targeted drug delivery in cancer cells. Utilizing this strat- the existing NPs platform, which could be helpful in a tumor egy, Xupeng et al. have developed a multifunctional nano- specific therapy (Arachchige et al. 2017). composite consisting of IONPs and shown applications in Jia et al. constructed a nanocarrier with PLGA polymer the diagnosis, targeting, and chemo and photothermal ther- encapsulating IONPs and DOX. The drug internalization apy of cancer (Xupeng Mu 2017). The nanocomposite was study was performed in multiple cancer cell culture models designed by conjugating EGFR antibody on polydopamine- such as Lewis lung carcinoma (LLC), human osteosarcoma coated Fe O NPs and loaded with DOX. This nanocom- (OS-732), and murine-leukemic monocyte–macrophage 3 4 posite exhibited pH and NIR triggered drug release, which (RAW 264.7) cell lines and results revealed that IONPs- resulted in effective inhibition of colon cancer cells (DLD- DOX combination was internalized in cells in higher amount 1, exhibiting overexpression of EGFR) due to synergistic with respect to when DOX alone was used. In addition, a chemo and photothermal therapy. Additionally, these nano- higher concentration of IONPs-DOX internalization induced composites were also utilized for T contrast generation to apoptosis in LLC cell line. Under In vivo experiments, follow the tumor growth by MRI scanning under in vivo results showed that more anti-tumor effect was seen with experimental condition. In another attempt, Arachchige et combination therapy, which was further improved in pres- al., synthesized dextran coated IONPs and conjugated them ence of external magnet (Jia et al. 2012). with DOX and fluorescein isothiocyanate (Fig. 11). The so Fig. 11 Synthesis and functionalization of superparamagnetic iron entry (15 min) and intracellular release and accumulation of the oxide (SPIO) nanoparticles for rapid cellular entry and release of the cancer drug in the nucleus (white arrow head) of human pancreatic cancer drug Doxorubicin (DOX) in human pancreatic cancer cells. cancer Mia Paca-2 cells.. Reprinted with permission from ref (Arach- Dextran coated Fe O core with DOX (red fluorescence) and FITC chige et al. 2017) Copyright (2017) Elsevier 3 4 (green fluorescence) surface conjugation chemistry, and the rapid 1 3 3 Biotech (2018) 8:279 Page 15 of 23 279 The blood–brain barrier is a semipermeable membrane involves the breakdown of bone tissues, can improve the that protects neural tissue from toxins and exogenous sub- bone damage. To overcome the effect a composite nano- stances. The tight junctions in the endothelial cells around system was developed using F e O NPs with alendronate 3 4 the capillaries are responsible for the barrier formation. Dau- drug for treating osteoporosis. In this novel strategy, after norubicin (DNR) is a potent topoisomerase inhibitor and the delivery of NPs near osteoclasts (OCs) cells, a dose of used as an effective chemotherapeutic agent to treat leukemia radiofrequency was applied to induce thermolysis to OCs. It and neuroblastoma. Xuhua et al. synthesized DNR loaded was also suggested that these multifunctional NPs with their Fe O NPs and found the formulation was efficient enough drug delivery, thermolysis, and contrast (MRI) generation 3 4 to cross the blood–brain barrier which separates the circulat- ability can be used as a potential therapeutic and imaging ing blood from the brain. Results suggested that the com- agent for osteoporosis (Lee et al. 2016). bination therapy can trigger apoptosis in glioma cells and thus used as a promising agent to cross the otherwise imper- meable blood–brain barrier and treat brain tumors (Xuhua Gene delivery applications Mao 2016). Experimental data indicated that the formula- tion increased the barrier permeability through opening tight Gene delivery is a therapeutic technique for the delivery of junctions via controlling the expression of cell–cell adhe- nucleic acids instead of drugs or surgery to treat diseases. In sion proteins (E-cadherin, ZO-1, and Claudin-1). Homohar- general, it is a great challenge to deliver biological drugs like ringtonine (HTT) conjugated F e O NPs were synthesized siRNA, and plasmid DNA to target cells or tissues without 3 4 by Chen et al. to inhibit leukemia. Results showed NPs and being damaged by nucleases. Therefore, to overwhelm the drug combination enhanced the inhibitory effect on myeloid damage, nanocarriers like IONPs have been used to transport leukemia cell lines compared to HTT exposure alone. They the genes and release at the intended target sites (Kievit and found cell death was caused due to apoptosis and observed Zhang 2011). Borroni et al. developed a novel vector that cell cycle arrest at G0/G1 phase. Moreover, in vivo studies can deliver therapeutic genes for treating tumors. The gene- explained the combination worked efficiently to decrease the carrier contained IONPs conjugated with lentiviral vectors tumor volume compared to drug alone (Chen et al. 2016). A to deliver target gene at the area of interest (Fig. 12). To similar study explained the combination of F e O with adria- check the efficiency, this nanocarrier was injected with a 3 4 mycin or daunorubicin drugs showed a potential inhibitory reporter GFP gene (green fluorescent protein) into a tumor effect on lymphoma. A detailed study on Raji cells explained bearing mice and found sustained gene expression near the that the inhibition was due to induction of apoptosis which target areas. Their data suggest that in future LV-MNPs was further enhanced in the presence of NPs (Hongmei Jing can be successfully tailored to deliver therapeutic genes for 2010). Huilan et al. designed a nanocomposite encompass- selectively inhibiting the growth of tumors (Borroni et al. ing Fe O NPs and an anticancer drug ursolic methyl ester. 2017). Additionally, Mahajan et al. designed a novel IONPs 3 4 They demonstrated combination treatment increased the rate carrier to stop the progression of pancreatic cancer. IONPs of apoptosis in drug-resistant human leukemia cells (KA were coupled with siRNA (siPLK1) directed against Polo- cells) compared to the drug alone. The authors suggested like kinase-1 (cell cycle-specific serine-threonine-kinase). that this approach to inhibit the growth of drug-resistant Moreover, siPLK1-IONPs were conjugated to membrane cancer cells can be used as an alternative method to treat translocation peptide (myristoylated polyarginine peptides other cancers as well (Huilan Yue 2016). (MPAP)) for driving endosomal escape and mediating trans- Osteoporosis is a condition where bones become weak port to the cytoplasm and a tumor-selective peptide under- and brittle due to an imbalance between osteoblasts and glycosylated MUC1 (uMUC1)-specific peptide (EPPT1) osteoclasts (OCs). Thus, reducing the OCs activity, which to increase intracellular and tumor-specific delivery. The Fig. 12 Magnetic nanoparticles (MNPs) coupled with lentiviral vectors (LVs) as multifunctional and efficient tools to selectively induce transgene expression in solid tumor for therapeu- tic purposes. Reprinted with permission from ref (Borroni et al. 2017) Copyright (2017) Elsevier 1 3 279 Page 16 of 23 3 Biotech (2018) 8:279 experimental data revealed the significant accumulation of over traditional antibiotics as effective antimicrobials, as NPs and resulted in efficient PLK1 silencing that leads to microbes may not be able to develop resistance against tumor suppression through increased apoptosis (Mahajan these inorganic materials, therefore, it is expected that the et al. 2016). antimicrobial activity of nanomaterials would remain same, Cheong et al. synthesized IONPs-based carrier loaded even after multiple uses, which is one of the biggest limi- with water-soluble chitosan and linoleic acid (SCLNs) for tations with antibiotics. Among nanomaterials, IONPs are targeting hepatocytes. Authors confirmed the NPs localiza- well explored as an effective antimicrobial candidate. Stud- tion in the liver cells by injecting a nuclear isomer (Tech- ies on IONPs showed potential antimicrobial activity and netium-99m) labeled SCLNs in mice using nuclear and literature studies revealed citrate coated Fe O NPs have 3 4 magnetic resonance imaging. Further SCLN/enhanced GFP an inhibitory effect on Escherichia coli, Bacillus subtilis, (pEGFP) complexes transfected in primary hepatocytes, Candida albicans, Aspergillus niger and Fusarium solani intravenous administration in mice showed a significant (Arakha et al. 2015; Nehra et al. 2018). Further, Patra et al. increase in GFP expression. In addition, the gene silencing applied green synthesis for the synthesis of F e O NPs from 3 4 was effectively achieved by injecting SCLN complexes con- corn plant extract and explained that NPs exerted a syn- taining specific siRNA into mice. Thus, the results suggested ergistic antibacterial and anticandidal activity (Patra et al. that SCLNs can be used as a useful platform for imaging and 2017). In another attempt, a green chemistry approach using gene delivery simultaneously (Cheong et al. 2009). Couroupita guianensis fruit extract was applied to synthe- In addition, Ling-Feng et al. evaluated the use of IONPs size Fe O NPs and the particles exhibited potent bacteri- 3 4 as ideal gene-carrier for PTEN (Phosphatase and tensin cidal action on several human pathogens (Gao et al. 2017). homolog) gene delivery to reverse cisplatin-resistance in Additionally, Ismail et al. synthesized IONPs (α-Fe O ) and 2 3 lung cancer. PTEN acts as a tumor suppressor gene and its determined their antibacterial activity against Gram-positive inactivity causes the development of several cancers. A549/ and Gram-negative bacteria and stated that IONPs can cap- CDDP (cisplatin-resistant) cells were transfected with wild ture Staphylococcus aureus through magnetic field effect PTEN gene expression plasmid (pGFP-PTEN) using IONPs (Ismail et al. 2015). Arokiyaraj et al. have developed IONPs and liposomes as carriers. It was observed The IONPs medi- treated with Argemone mexicana L. leaf extract and showed ated PTEN transfection showed higher efficiency and more a significant colony growth inhibition against Escherichia PTEN expression compared to empty liposome-mediated coli and Proteus mirabilis (Arokiyaraj 2013). As discussed transfection. Further, PTEN transfection increased the apop- above, more strategies could be devised to develop synergis- totic cell population and enhanced the sensitivity of A549/ tic IONPs platform, which can be used as a carrier system to CDDP cells to cisplatin indicating PTEN can be an effective treat microbial diseases in future. target against cisplatin-resistant lung cancer cells (Ling-feng Min 2012) (Table 4). Summary and future perspectives Iron oxide nanoparticles as broad spectrum IONPs with their magnetic characteristics and contrast antimicrobial agent have already successfully applied in areas of biomedicine, including diagnostics as a probe (MRI scanning) for detec- Although IONPs have shown tremendous applications tion of diseases or disorders in the brain, cardiovascular, in drug delivery, phototherapy, and chemotherapy, they liver, blood vessels and other vital organs. Moreover, with have also found overarching potential as the antimicrobial advancements, IONPs are prepared in combinations to and antifungal agent. In the context of drug resistance in achieve multiple functions in a single stage like T and microbes, the developments of new drugs or novel strategies T MRI, and PET/CT/NIRF/MRI/PA imaging. Recently for efficient destruction of these pathogens need immedi - IONPs-based nanohybrids were tuned for hyperthermia ate attention. It is well known that antimicrobial resistance and PTT, where even low concentrations are capable to poses a catastrophic threat to humans because if it continues enhance the heat generation at the tumor site and can to grow with the current pace for 20 more years, it is esti- be efficiently used for cellular therapies. In bio-sensing, mated that people visiting hospitals for even minor surgery advances in Nanohybrid IONPs synthesis paved a path to may die due to an ordinary microbial infection, which cannot introduce enzyme mimetics, possessing peroxidase, oxi- be treated by antibiotics. It is estimated that the number of dase, and catalase-like activities. In addition, the nano- deaths due to microbial infection would surpass the mor- hybrids or conjugated NPs simplified the detection of tality due to cancer or diabetes in few decades. Therefore, biomolecules in a single step and laid the foundation to novel antimicrobials are needed to avoid these circumstances create novel nano-sensors and nano-devices. Further to in near future. Nanomaterials offer several advantages overcome the obstacles in cancer and multi-drug resistant 1 3 3 Biotech (2018) 8:279 Page 17 of 23 279 Table 4 Summary of iron oxide NPs applications in drug delivery and gene delivery Nanoparticle/material Size (nm) Applications/results References IONPs coated with 2-deoxy-d -glucose Pore size: 12 NPs enhanced chemo-radiotherapy effi- Pirayesh Islamian et al. (2017) and DOX ciency in breast cancer cells through targeting. Results showed the com- bined NPs treatment with doxorubicin and 2-deoxy-d -glucose boosted the breast cancer cure through improved radiotherapy Fe O NPs 9 Used for treating tumors through cry- Ye et al. (2017) 3 4 oablation therapy. Results indicated MCF7 cells were killed efficiently by cryoablation Fe O NPs @PEG, folate and cisplatin ~ 10 Used for ligand-mediated targeting Yan Zhang (2014) 3 4 (Folic acid-Polymer conjugated Fe O and chemotherapy. Cisplatin-loaded 3 4 NP with cisplatin) NPs showed concentration dependent cytotoxicity in HeLa cells. Moreover folate conjugation exhibited more cytotoxicity compared to non-conju- gated NPs DOX encapsulated Fe O ~ 12 Used as a nano-carrier for anticancer Ebrahimi et al. (2014a, b) 3 4 drugs like doxorubicin. NPs can be applied as a chemotherapeutic system for treating lung cancers Polydopamine coated Fe O with EGFR ~ 60 Used as a multifunctional composites in Xupeng Mu (2017) 3 4 antibody and DOX diagnosis (MRI imaging) and cancer treatment (chemo-photo thermal therapy). Results showed the combi- nation therapy is efficient enough in killing EGFR expressed tumor cells (colon cancer) Dextran coated IONPs with FITC and ~ 8 Used for drug delivery with multimodal Arachchige et al. (2017) DOX imaging (MRI and FITC Fluores- cence) and cancer treatment (drug and hyperthermia) Can be applied for treating pancreatic cancers MNPs encapsulated in PLGA with MNPs: 4–6 Used as a nano-carrier for drugs like Jia et al. (2012) DOX DOX-MNPs: 200–300 doxorubicin. Results showed DOX- MNPs were internalized in to lung cancer cells (Lewis lung carcinoma cells) and induced apoptosis. Moreo- ver in vivo studies revealed more anti-tumor activity in presence of an external magnetic field DOX loaded Fe O -reduced graphene 8–10 Showed maximum inhibition of HeLa Gupta (2018) 3 4 oxide cells with hyperthermia assisted treatment Daunorubicin loaded Fe O NPs 100 Used to treat brain glioma. Results Xuhua Mao (2016) 3 4 showed this drug loaded NPs can be efficiently delivered into blood brain barrier and can act as promising drug to treat blood tumors Homoharringtonine conjugated Fe O 11.2 Used for in vitro and in vivo chemo- Chen et al. (2016) 3 4 NPs therapy towards hematological malignancy. Results indicated drug conjugated MNPs injected in tumor bearing mice (leukemia) showed a significant decrease in tumor growth compared to drug treatment alone 1 3 279 Page 18 of 23 3 Biotech (2018) 8:279 Table 4 (continued) Nanoparticle/material Size (nm) Applications/results References Liposome with paclitaxel and SPIONs 159–168 Comprising both MRI and antitumor Zheng et al. (2018) characteristics. Results showed the tumor growth was supressed in MDA-MB-231 tumor-bearing mice compared to controls Fe O NPs with adriamycin and dau- – Used as a combination therapy to treat Hongmei Jing (2010) 3 4 norubicin lymphoma. Results revealed increased apoptosis in Raji cells and upregu- lation of p53, down regulation of NF-kB was observed with NPs drug combination treatment Cetuximab-IONPs – Both in vitro and in vivo studies Freeman et al. (2018) revealed anti-tumor efficiency against gliomas Fe O NPs with urosilic metyl esters 10 Used as anti-cancer agent for leukae- Huilan Yue (2016) 3 4 mia. NPs and the drug combination induced apoptosis in drug-resistant human leukemia KA cells Fe O NPs with alendronate ~ 20 Used for treating osteoporosis. Results Lee et al. (2016) 3 4 showed NPs-drug exposure decreased the survival rate of osteoclasts com- pared to control cells and osteoblasts LV-MNPs 10–20 Can be applied as a combined therapeu- Borroni et al. (2017) tic system to target gene expression in cancer cells IONPs with siRNA IONP core: 9.81 ± 3.73 Used for treating pancreatic cancers. Mahajan et al. (2016) Conjugated IONs: 12.3 ± 1.4 The nano-conjugate with siRNA resulted in efficient PLK1 silencing and halted the tumour growth with increase in apoptosis IONPs loaded chitosan–linoleic acid 12 Used as a gene delivering system for Cheong et al. (2009) NPs targeting hepatocytes and gene silenc- ing IONPs with PTEN gene – Used as gene carriers for PTEN and Ling-feng Min (2012) applied for reversing cisplatin-resist- ance in lung cancer diseases, multifunctional IONPs were being designed for platform, which combines therapeutics with diagnostics. diagnosis, targeting, nanocarrier, chemo and phototherapy Such attempts would primarily make the diagnosis pro- agents. In conclusion, more progression in the novel syn- cesses simpler, speedier and less invasive. Personalized thesis of nanocomposites with multifunctional modalities medicine is also gaining attention and it is expected that can find better ways to use IONPs as nano-theranostic enti- the integration of nanotechnology could result in over- ties in biomedicine. The future of IONPs in biomedical arching outcomes. In coming years, multifunctional IONPs applications holds great promise especially in the area of would be an attractive material for biomedical applications disease diagnosis, early detection, cellular and deep tis- and may change the usual business model of pharmaceuti- sue imaging, drug/gene delivery as well as multifunctional cal industries. therapeutics. Although, Feraheme (US FDA approved) is Acknowledgements The financial assistance for the Centre for Nano- being used by the consumers, more of such IONPs-based technology Research and Applications (CENTRA) by The Gujarat materials need to be researched and made available to the Institute for Chemical Technology (GICT) and the funding from the consumer market. The current emphasis of molecular med- Department of Science and Technology-Science and Engineering icine is to develop more novel tools, which can be used Research Board (SERB) (Grant no.: ILS/SERB/2015-16/01) to Dr Sanjay Singh under the scheme of Start-Up Research Grant (Young for early-stage disease diagnosis and more of point-of- Scientists)—Life Sciences are gratefully acknowledged. Dr Singh is care diagnostics. Integration of nanomaterials, especially also thankful for the financial support provided by the Ahmedabad IONPs, could extend the construction of the theranostic University as Seed Grant (AU/SG/SAS/DBLS/17-18/03). 1 3 3 Biotech (2018) 8:279 Page 19 of 23 279 Borroni E, Miola M, Ferraris S, Ricci G, Zuzek Rozman K, Koste- Compliance with ethical standards vsek N, Catizone A, Rimondini L, Prat M, Verne E, Follenzi A (2017) Tumor targeting by lentiviral vectors combined with Conflict of interest The authors declare no conflict of interest. magnetic nanoparticles in mice. 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Published: Jun 1, 2018
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