Magnetic Nanoparticles: Current Trends and Future

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REVIEWARTICLE

Magnetic Nanoparticles: Current Trends and Future Aspects in Diagnostics and Nanomedicine Naga Veera Srikanth Vallabani1, Sanjay Singh1,3,* and Ajay Karakoti1,2,* 1 Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad 380009, Gujarat, India; 2School of Engineering and Applied Science, Ahmedabad University, GICT Building, Central Campus, Navrangpura, Ahmedabad 380009, Gujarat, India; 3Hospital of the University of Pennsylvania, Department of Radiology, Philadelphia, PA 19104, United States

ARTICLE HISTORY Received: July 31, 2018 Revised: September 23, 2018 Accepted: October 10, 2018 DOI: 10.2174/1389200220666181122124458

Abstract: Background: Biomedical applications of Magnetic Nanoparticles (MNPs) are creating a major impact on disease diagnosis and nanomedicine or a combined platform called theranostics. A significant progress has been made to engineer novel and hybrid MNPs for their multifunctional modalities such as imaging, biosensors, chemotherapeutic or photothermal and antimicrobial agents. MNPs are successfully applied in biomedical applications due to their unique and tunable properties such as superparamagnetism, stability, and biocompatibility. Approval of ferumoxytol (feraheme) for MRI imaging and the fact that several Superparamagnetic Iron Oxide Nanoparticles (SPIONs) are currently undergoing clinical trials have paved a path for future MNPs formulations. Intensive research is being carried out in designing and developing novel nanohybrids for multiple applications in nanomedicine. Objectives: The objective of the present review is to summarize recent developments of MNPs in imaging modalities like MRI, CT, PET and PA, biosensors and nanomedicine including their role in targeting and drug delivery. Relevant theory and examples of the use of MNPs in these applications have been cited and discussed to create a thorough understanding of the developments in this field. Conclusion: MNPs have found widespread use as contrast agents in imaging modalities, as tools for bio-sensing, and as therapeutic and theranostics agents. Multiple formulations of MNPs are in clinical testing and may be accepted in clinical settings in near future.

Keywords: Magnetic resonance imaging, computer tomography, positron emission tomography, photoacoustic tomography, nanozymes, biosensors, SPIONs, iron oxide nanoparticles.

*Address correspondence to this author at the Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Central Campus, Navrangpura, Ahmedabad 380009, Gujarat, India; E-mails: [email protected], [email protected] (S. Singh); [email protected] (A. Karakoti)

magnetization level and change in magnetic induction under the influence of an external magnet. Based on the magnetic susceptibility, materials (including NPs) are categorised as diamagnetic, paramagnetic, ferromagnetic, ferrimagnetic, antiferromagnetic and superparamagnetic materials [7]. The absence of unpaired electrons in diamagnetic materials (gold, silver, bismuth, mercury, copper, some plastics) results in zero magnetic moment and is repelled by a magnetic field. In contrary, paramagnetic materials (aluminium, titanium, magnesium, lithium, oxygen) forms a weak magnetic moment, but do not retain the magnetic properties in absence of magnetic field. Materials such as iron, nickel and cobalt are ferromagnetic and have a net magnetic moment due to the presence of unpaired electrons. In the presence of the magnetic field, their domains align in the direction of the applied magnetic field and tend to gain large magnetic moment, and remains magnetized even after the external magnet is removed [11, 12]. Fe3O4, a ferrimagnetic material, consists of two different ions (Fe2+ and Fe3+) where the opposing moments are unequal leaving a net spontaneous magnetic moment. In antiferromagnetic materials (NiO, CoO, MnO, FeMn and CuCl2) magnetic moments with equal magnitude and opposite spins results in zero magnetization. However, ferrimagnetic and antiferromagnetic materials show the same behaviour like ferromagnets in presence of an external magnetic field [11]. Superparamagnetism appears in small ferrimagnetic or ferromagnetic NPs (size range ~ 3-50 nm) and acts as a paramagnet in presence of a magnetic field, though their magnetic susceptibility is much higher compared to paramagnetic materials [13]. For biological applications, medical diagnosis and drug delivery MNPs are preferred to be in superparamagnetic state at room temperature and

© 2018 Bentham Science Publishers

1. INTRODUCTION MNPs, with unique characteristics such as small size, electromagnetic properties, colloidal stability and bio-compatibility have been widely investigated for versatile applications in the development of novel contrast agents for imaging, and drug or gene delivery, as well as fabrication of biosensors [1-3]. Recently, the advancement in the precise synthesis and surface functionalization of MNPs has imparted them multi-functional properties. These advancements have captivated the researchers to explore further characteristics of MNPs especially in the fields of biomedical applications and nanomedicines. At nano scale, functionalized MNPs exhibit paramagnetic or superparamagnetic behaviour and tend to aggregate in the presence of external magnetic field; however readily disperse upon the removal of magnetic source. This magnetic behaviour allows MNPs to play a key role in biomedicine including Magnetic Resonance Imaging (MRI), targeted drug delivery, hyperthermia and bio-sensing [4-8]. Surface stabilization of MNPs with ligands is essential for their applications and serves a dual role of preventing agglomeration and avoiding oxidation. In the absence of protective ligands as coating, MNPs tend to oxidise that can lead to loss of magnetic properties [9, 10]. Magnetic properties of nanomaterials can be determined by factors like susceptibility and permeability, which explains

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need colloidal stability at physiological conditions [1]. For biomedical applications, characteristics like size, coating properties and core material type determine the toxicity and biocompatibility of MNPs. Among MNPs, Co and Ni are considered toxic because of their susceptibility to oxidation and acid erosion. In comparison, Iron Oxide Nanoparticles (IONPs) are being used extensively in biomedical applications from several years [1, 7] though with limited applications. Hence, to increase the efficacy of MNPs in biomedical applications novel strategies of functionalization and coatings (with polymers, surfactants, biomaterials or inorganic materials (like gold, silica etc.)) are required to increase biocompatibility, colloidal stability, and avoid phagocytosis (by reticuloendothelial system) [14-19]. At present, NPs used in nano drug formulations comprise nanocrystals, liposomes, micelles, biomolecules, metal oxides and inorganic materials. Amongst different nanomaterials, metal oxide NPs are being investigated copiously for their application in theranostics. Further, nano-drugs have created a niche in clinical practice, and many drugs are under clinical investigations for a wide range of applications [20, 21]. However, to reach the market level from pre-clinical stages they face several challenges such as characterization issues, toxicity issues, market value and lack of suitable regulatory guidelines [21]. IONPs and SPIONs are involved in numerous clinical studies and a few are approved by U.S Food and Drug Administration (FDA) in iron replacement therapies, as MRI contrast agents in imaging and for magnetic hyperthermia [22, 23]. The iron replacement formulations contain iron oxide coated with polymers like sucrose (Venofer), dextran (Dexferrum, Infed) and sodium ferric gluconate complex (Ferrlecit) to treat anaemia associated with chronic kidney disease (CKD) [21, 22, 24]. SPIONs like ferumoxytol (carbohydrate coated), Resovist (carboxydextran coated), GastroMARK (silicon coated) and Feridex (dextran coated) formulations have received FDA approval. Feraheme (ferumoxytol) is available in the market for treating anemia in adults suffering from CKD and for limited MRI applications such as MR angiography in renal failure patients and Clariscan (PEGylated starch coated IONPs) for liver lesions imaging is under clinical trials [23, 25]. In addition, hyperthermia agent Nanotherm for treating glioblastoma tumours was approved and Magnablate I for treating bladder or prostrate caner was under clinical use [23]. Despite the growing popularity, there are some withdrawn products like GastroMARK and Feridex from the market or products like Nanotherm is only available in few countries due to side effects or lack or users [21, 24]. Therefore, new strategies or novel MNPs (such as doped materials) should emerge with multifunctional modalities having optimized magnetic properties, minimum toxicity and improved pharmacokinetic profiles to pass in clinical trials and for their long-term usage [26]. Based on the novel multi-functional properties of MNPs, the present review is focused on MNPs/hybrid MNPs and their role in biomedical applications including imaging, targeting and delivery, biosensors and nanomedicine. 2. ROLE OF MNPS IN IMAGING Biomedical imaging modalities comprise Magnetic Resonance Imaging (MRI), Ultra Sound (US), Computed Tomography (CT), Positron Emission Tomography (PET), Photo Acoustic Tomography (PA or PAT), Single-Photon Emission Computed Tomography (SPECT) imaging and fluorescence imaging [27-29]. These modalities gained utmost interest in the last few decades and are applied clinically to achieve accurate and sensitive detection of diseases and disorders. To improve the accuracy of measurement and to augment the necessity of high-resolution imaging, multi-modal methods and novel contrast agents are developed to fulfill the clinical needs. Amongst other well-known contrast agents [30] MNPs are known for their versatile properties and can be utilised as a multimodal imaging platform (MRI–CT/PET/SPECT) for better sensitivity and spatial resolution [31, 32]. MNPs can be tagged with secondary imaging moieties for enhancing the signals or can be applied in

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emerging techniques like Magneto-Photoacoustic Imaging (MPA), Magnetic Particle Imaging (MPI) and Magneto-motive Ultrasound Imaging (MMUS) for visualizing the localized MNPs [33]. 2.1. MNPs as Contrast Agent in MRI Imaging The non-invasive technique MRI works with a similar principle of nuclear magnetic resonance and produces three-dimensional anatomical images upon perturbation with radio frequency waves. The technology is well suited for clear representation of soft tissues or non-bony parts like muscles, tendon, ligament, nerves, brain and spinal cord. Hydrogen is a common atom available in the body (from water and fat) and has a proton spin resulting in the development of a magnetic field of the proton. Exposure to a strong magnetic field (present in MRI scanner) results in an equilibrium magnetization that aligns most of the protons in the direction of the external magnetic field (demonstrated as longitudinal magnetization in MRI or Z axis). When a radio frequency pulse resonating at a frequency (Larmor frequency) conductive for transfer hits the hydrogen, the protons can absorb the energy resulting in the rotation or their spin perpendicular to longitudinal magnetization axis (termed transversal magnetization or XY axis) at an angle called as flip angle. Once the pulse is switched off, the protons tend to relax and revert back from XY axis to Z-axis leading to longitudinal relaxation (T1) and transversal relaxation (T2) processes to occur. In T1 relaxation the protons which are in high energy state relax to lower energy state with the release in energy to surrounding tissues and return to longitudinal magnetization exponentially. The time required for longitudinal magnetization to recover 63% of its original value is known as T1 relaxation time. Similarly, the pulse off causes dephasing (loss in phase synchronization) and leads to a decrease in transverse magnetization called transverse decay. Hence, the time taken for transverse magnetization to decay to 37% of its initial value is termed as T2 relaxation time. The relaxation time is considered to be tissue dependent. There also exists T2* which arises due to additional inhomogeneity in the magnetic field. This inhomogeneity primarily results from intrinsic defects in the magnet, however since T2* is an order of magnitude faster than the intrinsic T2 decay, MNPs have been developed as T2 contrast agents with an ability to induce field inhomogeneity [34]. The most commonly used contrast agents in MRI are Gadolinium (paramagnetic) based agents which were first approved in 1988 for clinical use. They have a potential role in T1 contrast imaging through shortening the T1 relaxation time of protons. However, the side effects of gadolinium limited their usage and resulting in a need to develop novel contrast agents with minimum toxicity and multifunctional properties [35]. For MRI imaging, contrast agents possessing paramagnetic properties gives a faster T1 relaxation rate (R1, the inverse of T1, s-1) and produces brighter images (longitudinal relaxation). However, ferromagnetic and superparamagnetic NPs have faster T2 relaxation rate (R2, the inverse of T2, s-1) and yields darker contrast (transverse relaxation) [33, 36]. Studies indicate that contrast agents like SPIONs with large hydrodynamic diameter (~ 16 to 200 nm) exhibit T2 contrast ability, as saturation magnetization increases proportionally with an increase in size. Furthermore, efficient T2 relaxivity can be achieved by modulating the magnetic saturation and radius of NPs which is largely dependent on the shape [33]. However compared to T2 contrast, small sized SPIONs (less than 10 nm) have revealed potential T1 capabilities due to their high surface to volume ratio. T1 contrast was also found to be by differences in morphology of NPs [33, 37]. In general, metallic NPs like iron, cobalt, nickel and their alloys comprise high magnetization extent than oxide NPs and hence several efforts have been made to combine synthesis of nanomaterials with different cores or coatings to enhance T1 or T2 contrast abilities of nano hybrids [38]. Clustering of MNPs compared to individual NPs can enhance the T2 relaxivity in MRI and it was hypothesized that polynuclear

Magnetic Nanoparticles

clusters (with different size and shape) augment the magnetic field inhomogeneity due to reduced symmetry among MNPs. This could generate a high performance T2 contrast. To prove this an in vivo study was carried in a liver tumour model injected with HepG2 cells in mouse liver. A tumour lacks macrophages (kupffer cells) and are less likely to uptake the IONPs and hence show minute contrast compared to the surrounding tissues. Finally a clear boundary separating the tumour from the adjacent tissue with dark T2 signal was observed in MRI imaging. Studies carried out with known FDA approved agent ferumoxytol depicted less T2 contrast than clustered MNPs [34]. Ultra-small nanohybrids composed of metal or metal alloy core (Fe and CoFe) and doped metal oxide (zinc oxide and aluminium oxide) as core shell were designed for MRI imaging. These Fe(1and (CoFe)(1-x)Alx@Al(1-y)(CoFe)yOx)Znx@Zn(1-y)FeyO-(OH)z (OH)z nanohybrids exhibited excellent magnetic and surface properties which enhanced dual T1/T2 weighed imaging effects. The dual mode MRI imaging was endowed by surface chemical properties and unique magnetic properties due to interface magnetic coupling, change in magnetic anisotropy (by core alloying) and by doping of metal oxide shells. Moreover, the composite displayed better positive contrast (T1 imaging) compared to commercially available gadolinium contrast agents and SPIONs [39]. Cobalt as a core has also been reported in less exotic nanohybrids with good performance. Cobalt zinc ferrite NPs coated with Dimercaptosuccinic acid (DMSA) to ensure biocompatibility was designed to give high MRI contrast. The study evaluated the ability of bare and conjugated NPs as contrast agents in prostate cancer cells (PC3 and DU145) and found enhanced T2 weighed signals with an increase in NPs concentration. Thus the results confirmed both bare (CZF-MNPs) and coated NPs (CZF-MNPs-DMSA) are suitable for T2 contrast MRI imaging [38]. Similarly, Zn0.5Co0.5Fe2O4 (zinc substituted cobalt-ferrite) NPs application in in vitro, in vivo data revealed their potential role as T2 contrast agent in MRI imaging [40]. Amongst other transition metals Nickel nanohybrids have also been tried as a magnetic core. Chitosan-coated nickel ferrite (NiFe2O4) NPs (cylindrical in shape) which are suitable for both T1 and T2 contrast imaging in MRI were reported recently. Animal studies explained these NPs can be used as dual contrast agent based on the system or disease of interest considered. Moreover the ability to have both bright (T1 weighted imaging) and dark (T2 weighted imaging) contrast in the same system is an advantage compared to the conventional SPIONs where only single imaging is possible [41]. Similarly, an earlier study revealed that dextrancoated nickel ferrite (NiFe2O4) NPs can also show dual T1 and T2 contrast. Further, animal studies showed they have better imaging characteristics compared to commercial gadolinium-based contrast agents [42]. A nanohybrid, dextrin coated Zn0.5Ni0.5Fe2O4 NPs, was found suitable for T2 weighted imaging and thus designed for MRI through conjugation with bioactive ligands for targeted imaging [43]. The role of the size of nanoparticles in obtaining a good MRI contrast was also investigated using casein coated Fe5C2. The casein coating resulted in water solubility and stability of NPs was suggested to have T2 contrast with better transverse relaxivity for liver imaging. From a comparison of NPs of different sizes (5, 14 and 22 nm), casein coated 22 nm Fe5C2 NPs exhibited superior T2 contrast compared to traditional IONPs [44]. The uptake amount of NPs is similar for all the sizes, but bigger size Fe5C2 NPs was observed to be accumulated in liver and spleen due to the uptake by kupffer cells and splenocytes of respective organs. Further, 5 nm NPs accumulated in kidneys due to the possible renal clearance attributed to their small size. Rare earth metals have also been used to form magnetic nanohybrids by blending europium, cobalt and iron oxide. A nano-probe

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(FA/Si-CFEu) for multimodal imaging with MRI and fluorescence (due to europium) capability was designed by encapsulating europium Cobalt Ferrite (CFEu) NPs into poloxamer coated mesoporous silica and finally decorated with folic acid for facilitating uptake in monocytes. In vivo studies demonstrated that FA/SiCFEu displayed enhanced T2 signal in macrophage-rich regions like liver and spleen (RES) compared to USPION (ultrasuperparamagnetic iron oxide NPs). Further, to determine the NPs distribution in different tissues, Iba-1 antibody (red fluorescence) was used as a probe for macrophage detection. A clear green (NPs Fluorescence) and red fluorescence in liver and spleen indicated NPs localization in tissue macrophages. Thus based on their T2 MRI and fluorescence ability FA/Si-CFEu can be used as a potential multi-imaging platform and also as a theranostic construct (through incorporating desired drug) in future [45]. As discussed earlier that the magnetic contrast also depends upon the shape of the NPs. In a comparative study of nanorods and nanoparticles, it has been found that the induced magnetic field in a nanorod is higher due to anisotropic morphology and higher surface to volume ratio compared to spherical nanoparticles and resulted in higher R2 relaxivity compared to spheres [46]. In another attempt to influence the magnetic field by shape and structure, flower-like cobalt ferrite clusters (CoFe2O4) were synthesized using starch as a complexing agent and CTAB structure as directing agent. In an aqueous phantom assay, data showed that CoFe2O4 combination can be used as an efficient T2 contrast agent for MRI imaging compared to NPs without coating. Further, this multicore assembly can be applied for tumour targeting and also as drug carrier with proper functionalization [47]. While development of multiple cores is important in obtaining high tissue contrast during the imaging, any novel hybrid construct can be applied based only on their biocompatible nature. The essential property of a biocompatible material is the absence of immunological response or toxicity after administration in the body. In order to make biocompatible MNPs, conjugation or coating of MNPs using biologically compatible molecules is desirable. Polymers like dextran, chitosan, phospholipids and polyethylene glycol are used as biocompatible surface coatings to render chemical biological stability along with reduced toxicity and increased circulatory half-life of NPs in the body. Further, metal coating with gold was shown to functionalize SPIONs with thiol groups for linking ligands suitable for optical properties in visible and infrared regions [48, 49]. Presently, emphasis on target-specific MNPs as contrast agents have become predominant for improving specificity, sensitivity, detection and treatment of cancer and other diseases. A serious problem hindering cancer therapy is lack of selectivity to target tumours over normal cells and leading to side effects or complications. So to overcome the effects, new approaches are being implemented to specifically target the tumour cells. One such approach is through antibodies targeting their antigens, growth factors, hormones etc. In this aspect, ligands like folate a) folate (to target folate receptor expressed in ovarian, breast, lung and renal tumours), b) Epidermal Growth Factor (EGF) for targeting non-small cell lung cancer cells, colorectal and breast cancer cells expressing epidermal growth factor receptor (EGFR or HER1 in humans), and c) Prostrate Stimulating Membrane Antigen (PSMA) for targeting prostate cancer cells etc. can be decorated on MNPs for effective targeting in theranostics [50, 51]. Chitosan and folic acid coated SPIONs (SPIONP-CS-FA) for targeted MRI imaging in vivo were synthesised recently. In this construct, chitosan served as the modality that gives biocompatibility while folic acid was used to target the overexpressed folate receptors on the cancer cells. The study explained IONPs conjugated with biomolecules showed specific and higher uptake in HeLa cells (human cervical adenocarcinoma cells) due to the expression of folate receptors. Results in Wistar rat revealed that compared to other organs only liver tissues (due to the uptake of NPs by Kupffer


cells) showed dark contrast on T2 weighted images after NPs (SPIONP-CS-FA) injection. Hence, this NPs system can be applied as a potential contrast agent for target-specific tumour detection or for screening liver disorder [52]. Similarly, proline-rich amphiphilic peptide conjugated SPIONs were demonstrated for their role as a contrast agent in MRI. Cytotoxicity studies were carried in HUVEC (Human Vascular Endothelial Cells), MCF-7 (human breast adenocarcinoma) cells and nanocomposite efficiency as contrast agent was examined in Sprague-Dawley rats bearing mammary gland tumours. It was found that peptide coated IONPs accumulated in the tumours and can be applied as a promising T2 contrast agent (negative contrast). Although NPs were found in RES organs after injection, their signal intensity decreased after 1 hour and finally cleared from the RES system within two weeks confirming the biocompatibility and clearance of MNPs [53]. Zwitterion coated SPIONs (ZES-SPIONs) called exceedingly small IONPs made up of 3 nm core and 1 nm hydrophilic shell were found to have T1 contrast imaging capability in MRI. The zwitterionic property enabled low non-specific interactions with proteins and stability with respect to pH. These IONPs are free of gadolinium and exhibited a high T1 contrast and can be used as an alternative to Gadolinium Based Contrast Agents (GBCAs). The biodistribution of NPs was assessed by conjugating 59Fe radioisotope to ZES-SPIONs and injecting them in mice. Fluids collected from the mice post injection indicated the majority of IONPs were cleared via the renal route. Further ZES-SPIONs administration in animal model displayed strong T1 contrast in heart, vena cava, kidneys and bladder suggesting their role as a bright contrast agent in MRI. Data also revealed these SPIONs can be used for magnetic resonance angiography (blood vessels imaging) [37] (Fig. 1). Further, SPIONs coated with gold and methyl-polyethylene glycol (mPEG-core@ shell NPs) showed potential contrast agent ability for MR imaging. Gold shell coating provided the chemical stability (prevents agglomeration, corrosion and oxidation/reduction reactions of MNPs within hostile body fluids environment) and biocompatibility, mPEG layering was applied to prevent or reduce the recognition of NPs from RES. Prostate cancer cell line (LNCap) was injected in nude mice to induce tumors and after the tumours

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had grown 6-8 mm, nanocomplex was injected intravenously. Results confirmed that core shell NPs presented highly sensitive T2 weighted MR imaging and can have potential applications in visualizing tumours at an early stage [48]. In addition to diagnostic applications hybrid (alloy), MNPs have also been designed for theranostics applications. Ascorbic acid stabilized iron platinum NPs (Pt-FePt) exhibited therapeutic use and MRI imaging capabilities. Pt-FePt NPs displayed ROS generation mechanism via catalyzing decomposition of H2O2, to kill tumour cells and possessed enhanced T2 contrast capability for MRI. This system shows multi-functional biomedical applications at physiological pH compared to other ROS generation systems that work only at acidic pH [54]. In addition, studies revealed FePt NPs have better T2 contrast agent properties compared to conventional SPIONs [55, 56] and further signified weak ferromagnetic kale-like and superparamagnetic (cabbage like) Ni3S2/Ni nano hybrids can be utilized in T1 MRI imaging [57] (Table 1). 2.2. MNPs as Contrast Agent in CT Imaging Computer tomography is a non-invasive imaging technique used for generating cross-sectional images of the anatomy. CT scan uses the source of X-rays to detect tumours, clots, injuries or disorders in the head, lungs, heart, etc. CT is primarily based on the density of the tissue through which X-rays are passed and signal is measured from the attenuation coefficient (explains the amount of beam attenuated). The advantage of CT over conventional X-rays is the emitter rotates around the body to capture multiple images from different angles and the images or slices are stacked to form three dimensional pictures of the body. Further, overlapping structures can be removed from the generated images for clear identification (location) of abnormalities. Also, it is very useful for imaging complex fracture in bones and provides detailed information compared to conventional x-ray system. Recently, NPs based contrast agents like Au NPs, bismuth NPs and MNPs were designed to overcome the side effects of traditional agents (Iodine) and to impart better contrast [58-60]. The suitability of NPs for CT is based on having a high X- ray absorption coefficient for enhanced contrast imaging. For reference, X-ray absorption coefficient of platinum is

Fig. (1). a) Schematic illustrating the biodistribution of 59 Fe-labeled ZESSPIONs in mouse model. b) Graphical representation of percentage 59Fe-labeled ZESSPIONs remained in blood, urine and organs. A-C) T1 magnetic resonance angiography of a mouse injected with ZES-SPIONs indicating clear contrast of heart and blood vessels. With increase in time, positive contrast of cardiovascular system decreased with increase in bladder signal suggesting the renal excretion of NPs. Reprinted with permission from ref [37] Copyright (2017) PNAS.


Table 1.


Summary of MNPs applications as contrast agents in MRI imaging.

Nanoparticle/ Material

Size (nm)

Applications/Results

Reference

IONP clusters

85.7 - 129.2

Clustered MNPs can enhance T2 contrast of MRI compared to individual MNPs.

[34]

In vivo results showed clear distinction of tumour boundary from the adjacent liver tissue through T2 contrast imaging in mice. Zwitterion coated SPIONs

~3

ZES-SPIONs administration in to animal model (mice) displayed strong T1 contrast in heart, vena cava, kidneys and bladder suggesting their role as a bright contrast agent in MRI.

[37]

Gadolinium free alternative to Gadolinium based contrast agents with effective T1 contrast. Cobalt zinc ferrite NPs coated with DMSA

40

In vitro studies in PC3 and DU145 cells found enhanced T2 weighted MRI imaging with increase in NPs Concentration.

[38]

These NPs are suitable for T2 imaging but lacked T1 contrast capability. Nanohybrid exhibited both T1 and T2 weighted imaging MRI effect.

[39]

(CoFe)(1-x)Alx@Al(1-y)(CoFe)yO-(OH)z nanohybrid

2.42 ± 0.3

Zn0.5Co0.5 Fe2O4 NPs

3.9± 0.9

Potential role as T2 contrast agent in MRI imaging.

[40]

Chitosan coated nickel ferrite (NiFe2O 4) NPs

Cylindrical shape

These NPs are suitable for dual (T1 and T2) MRI imaging.

[41]

[42]

NiFe2O 4 NPs

The T1 and T2 relaxation rates are much higher compared to commercially available gadopentetate dimeglumine (Gadolinium based contrast agent).

Length 17 and width 4.4 Cylindrical shape

These NPs are suitable for dual (T1 and T2) MRI imaging.

Length 17 and width 4

The T1 and T2 relaxation rates are greater compared to commercially available Gd-DTPA-BMA (Omniscan) contrast agent.

Zn0.5Ni0.5 Fe2O 4 NPs

20.5 ± 3.2

These NPs are suitable for T2 weighted MRI imaging.

[43]

Casein coated Fe5C2 NPs

5-22

NPs exhibited superior T2 contrast in liver MRI imaging compared to traditional IONPs.

[44]

Europium cobalt ferrite (CFEu) NPs

~7.2

These NPs possess both T2 MRI and fluorescence ability and can be used as a potential multi-imaging platform.

[45]

Decoration of folic acid on these NPs increased sensitivity and specificity for MRI over conventional SPIONs. Flower shaped cobalt ferrite clusters (CoFe2O4)

8- 200

Can be used as an efficient T2 contrast agent for MRI imaging.

[47]

SPIONs coated with gold and methyl polyethylene glycol (mPEG-core@shell NPs)

~25

NPs presented highly sensitive T2 weighted MR imaging in nude mice injected with Prostate cancer cell line (LNCap).

[48]

Chitosan and folic acid coated SPIO NPs

11.48 ± 1.20

Results in Wistar rat revealed only liver tissue showed dark contrast (T2 contrast) compared to other organs after NPs injection.

[52]

Proline-rich amphiphilic peptide conjugated SPIONs

5.5 ± 0.6

Results indicated peptide coated IONPs accumulated in the tumours and can be applied as a promising T2 contrast agent (negative contrast).

[53]

Ascorbic acid stabilized iron platinum NPs (Pt-FePt)

1.9- 4

Pt-FePt NPs displayed ROS generation mechanism via catalyzing decomposition of H2O2, to kill tumour cells and possessed enhanced T2 contrast capability for MRI imaging.

[54]

FePt NPs

~9

These NPs possess better T2 (negative contrast) contrast agent properties.

[55, 56]

Showed higher T2-shortening effect compared to conventional SPIONs. Ni3S2/Ni nano hybrids

-

These cabbage like Ni3S2 /Ni nano hybrids can be utilized in T1 MRI imaging.

[57]

5


6.95 cm2/g at 50 keV, compared to Au (5.16 cm2/g at 100 keV) and iodinated agents (1.94 cm2/g at 100 keV) suggesting its ability as an efficient CT contrast agent [61, 62]. Hence, a combination of alloys (like Fe, Pt) can serve as a single module for multimodal MRI/CT imaging. FePt with different sizes (3, 6 and 12 nm) were monitored for application in CT/MRI as a dual-modality contrast agent. The study suggested NPs of all sizes were biocompatible and can be cleared from the body within one week. Further, FePt conjugated with antiHer2 antibody allowed the contrast agent to target Her2 (human epidermal growth factor receptor2) receptors overexpressed on breast tumors with better CT and T2 weighted MRI contrast. Overall 12 nm FePt NPs outperformed the other sizes in both MRI and CT imaging modalities due to their better contrast ability. However, localization of 3 nm NPs in the brain was higher compared to 6 and 12 nm particles that can pave a way forward in multimodal brain imaging applications [61] (Fig. 2). Strong magnetic properties of manganese were coupled with high x-ray absorption properties of tungsten to synthesize manganese tungstate nanoparticles conjugated with hyaluronic-acid (HAMnWO4 NPs). The single NPs system comprising Mn with unpaired electrons showed strong relaxation for MRI, tungsten with high atomic number offered efficient X-ray absorption coefficient for CT imaging. In vitro and in vivo results displayed that NPs possess effective CT and T1/T2 dual MRI imaging characteristics. Moreover, the multifunctional NPs showed a clear contrast in liver and renal structures in both modes of imaging [63] (Fig. 3). IONPs were successfully shown to develop tissue contrast using Ultrasonic Computed Tomography (UCT). These NPs were tested in an ex vivo tissue model and breast mimicking phantom. Results showed that IONPs can be used as an efficient contrast agent for ultrasonic breast imaging and UCT can be prescribed as a prescreening test to reduce the cost compared to MRI [64].

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2.3. Role of MNPs in PET and PA Imaging Positron Emission Tomography (PET) is a biomedical imaging technique that helps to reveal the metabolic processes in the body. The technique relies on the detection of gamma rays emitted from a radiotracer (radionuclides) injected in the body and the target areas show bright spots for a positive result. A PET scan is usually performed to detect brain disorders, heart problems and cancer. Further, the sensitivity of PET can uncover the disorders in the early stages which may not be possible by MRI and CT. Hence, hybrid technologies like PET-CT, PET-MRI are designed to map the images for better anatomical and functional understanding in a single frame [65, 66]. Photoacoustic Imaging (PA) uses light energy as the excitation source and detects the generated ultrasonic sound waves from the target, through ultrasonic sensors and processes to form images. As the light source is non-ionizing and imaging is cost effective PA can be used for continuous and repetitive imaging to monitor the progressing tumours or diseases. Moreover, PA can depict the functional changes and subsurface tissue structures with a resolution of up to 100 m. A study including MnFe2O4, Fe3O4 MNPs stabilized with aluminium hydroxide shell to impart hydrophilicity and later labelled with [18F]-fluoride or 64Cu-bisphosphonate conjugate for bimodal imaging (as contrast agents) in PET/MRI was conducted. Data from MRI revealed T2 contrast and PET imaging in a mouse with [18F]-NPs showed a slow release of [18F] from NPs, compared to no loss of radioactivity as observed with 64Cu labelled NPs at targeted sites of liver and spleen. Therefore, the high affinity for bisphosphonate towards Al(OH)3 can be utilised to conjugate novel radionuclides with NPs for better multimodal imaging [67] (Fig. 4). In another study, IONPs encapsulated with PEG, 1,4,7,10tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and glutamate-urea-lysine (GUL) conjugate (DOTA-IO-GUL) were developed.

Fig. (2). FePt NPs as dual modality contrast agent for MRI/CT. MRI/CT images of the mice bearing transplanted MBT2 tumour (tumour indicated by red arrow). Reprinted with permission from ref [61] Copyright (2010) American Chemical Society.

Fig. (3). Schematic showing the multimodal imaging capability (both T1/T2 MRI and CT) of HA-MnWO4 NPs. Reprinted with permission from ref [63] Copyright (2018) American Chemical Society.



7

Fig. (4). a) 64Cu(DTCBP) 2 structure (the bisphosphonate derivative used to bind 64Cu to NPs). PET/CT images of a C57BL/6 mouse after administered with 64Cu radiolabelled MnFe2O 4@Al(OH)3 , images showing the biodistribution of NPs, at 0-15 min (b) and 105-120 min (c). Reprinted with permission from ref [67] Copyright (2014) Elsevier.

plied for multi-modality PET/SPECT-MRI imaging in a single platform [70]. PEG stabilized biocompatible CoO NPs with synergistic PA and MR imaging capabilities were designed. In vivo studies depicted NPs produced an intense T2 weighted signal and a PA Z-axis resolution of 0.3 nm was achieved. Thus, the combined imaging can improve the three dimensional detection of diseases or lesions in the whole body [71]. Further, studies, explored a novel combination of MRI and PA to detect NPs in Pico molar (pM) concentrations. The nanosystem comprised of Co NPs layered with Au NP and their MRI data revealed T2 contrast till a minimum concentration of 2.5 pM in phantoms and 50 pM related to tissues. In addition, Au with their efficient optical absorption provided a better contrast with PA imaging too [72] (Table 2). With these recent advancements in nanomaterial research related to multifunctional MNPs, novel NPs having better biocompatibility, less toxicity and conjugated with multiple probes can be expected in the market in near future. Moreover such advancements can help the biomedical modalities to understand the diseases, disorders and cancers in detail and boost their detection at preliminary stages.

The bifunctional chelating agent DOTA was used for labelling 68Ga and GUL moiety for PSMA targeting (prostate specific membrane antigen). In vivo PET-MRI imaging in dual-tumour xenograft mouse model demonstrated that NPs were selectively localized to 22Rv1 (PSMA positive) but not in PC-3 (PSMA negative) tumors. Hence, results suggest that DOTA-IO-GUL NPs can act as dual modality probe for both PET/MR imaging [68]. A multimodal platform was proposed for magnetomotive ultrasound imaging (MMUS) using 68Ga-labelled magnetic nanoparticles which can also be implemented for pre-operative PET/MRI imaging. Radiation free MMUS allows the elimination of radiation exposure to the surgical personnel during operations. In vivo study was performed in Sentinel Lymph Node (SLN) rat model and imaging after 2 to 4 days of SPION injection revealed all the SLNs were detected by PET and 4 out of 6 rats were detected by MMUS. Thus stating MMUS with high spatial resolution can complement the standard pre-operative imaging techniques [69] (Fig. 5). A stable SPION multi complex with effective MRI-T2 contrast, radiolabelled by 67Ga for SPECT (single-photon emission computed tomography) or conjugated with radioisotope 57Co for PET imaging was synthesised. These labelled SPIONs were well dispersed, stable at the physiological condition and proved to be non-cytotoxic in 3T3-L1 (mouse embryo) and L6 (rat myoblast) cell lines. From the study, it was concluded that this multifunctional probe can be ap-

3. MNPS AS BIOSENSORS MNPs are well studied for their enzyme mimetic activity like peroxidase, catalase, oxidase and superoxide dismutase [73-78]. These nanoparticles also called as nanozymes gained superior interest over natural enzymes due to their cost effectiveness, multiple applications, and tolerance towards harsh environments like a wide range of pH, temperatures, denaturation and storage effects [79]. With artificial enzyme like activity, NPs were termed as nanozymes and utilised for detection of biomolecules like glucose, H2O2, glutathione, nucleic acids, urea, serotonin, creatinine etc., [74, 77, 8086]. The general mechanism followed for detection of analytes based on peroxidase or oxidase-like activity for colorimetric and electrochemical sensing is illustrated in Fig. (6). From last few decades use of electrochemical sensors is widely expanding in multiple areas of biosensing. Electrochemical methods used in biosensing are classified as amperometric, potentiometric and conductometric methods based on measuring current, voltage and impedance/conductance signals [79]. In this context, MNPs-modified electrodes are being used in detection of several biomolecules with minimum inference, high sensitivity and rapid response [80, 82, 83, 87-90]. For instance, in contrast to colorimetric assays, modified electrode with nanocomposites was produced to promote direct electron transfer from GOx for glucose detection (Fig. 7) [91]. Similarly, immuno sensor based on electrochemiluminescene was fabricated to detect tumour markers like -fetoprotein (Fig. 8) [92].

Fig. (5). a) PET/CT imaging in SLN rat model showing nanoparticle accumulation in sentinel lymph node and two iliac lymph nodes. b) MMUS image of the sentinel lymph node (enlarged area of the white rectangle from the PET/CT image). The colour-bar indicates the induced magnetomotive displacement shown on the right. Reprinted with permission from ref [69] Copyright (2017) Springer Nature.


Table 2.

Vallabani et al.

List of MNPs types and their applications in CT, PET and PA imaging.


Size (nm)


References

FePt NPs

3-12

Used for applications in CT/MRI as dual-modality contrast agent.

[61]

Manganese tungstate nanoparticles conjugated with hyaluronic-acid (HA-MnWO 4 NPs)

Plate like morphology with lengths 63122, width 3690 and thicknesses 1217

In vitro and in vivo results displayed that NPs possess effective CT and T1/T2 dual MRI imaging characteristics.

[63]

IONPs

~10

Results signified IONPs can be used as an efficient contrast agent for ultrasonic breast imaging.

[64]

MnFe2O 4, Fe3O4 MNPs

~10

Used for multimodal MRI/PET imaging.

[67]

IONPs encapsulated with PEG and DOTA

11.01 ± 1.541

In vivo results suggested DOTA-IO-GUL NPs can act as dual modality probe for both PET/MR imaging.

[68]

10 ± 2

Can be utilised for combined MMUS, PRT/CT imaging.

[69]

10-25

Results revealed this multifunctional probe can be applied for multi-modality PET/SPECT-MRI imaging in a single platform.

[70]

Pyramid shape

This biocompatible CoO NPs showed synergistic PA and MR imaging capabilities.

[71]

~80

In vivo studies depicted NPs produced intense T2 weighted signal and a PA Z-axis resolution of 0.3 nm.

~60

Can be utilised as a novel combination of MRI and PA to detect NPs in pico molar concentrations.

68

Ga-labelled SPIONs

SPION multi complex (-Fe2O3) CoO NPS

Co NPs coated with Au

Fig. (6). Schematic depicting the mechanisms involved in the peroxidase and oxidase like activity of MNPs and illustrating their biomolecule detection role through colorimetric and electrochemical detection methods. (ox indicates oxidation and red indicates reduction).

Glucose as a biomolecule has been a target analyte for demonstrating the use of MNPs in biosensors. As shown in Fig. (6), most of the glucose sensing approaches relies on the principle of generation of reactive oxygen species through the oxidase/peroxidase type activity of MNPs. The peroxidase phenomenon of IONPs relies on Fenton chemistry which involves the degradation of H2O2 during oxidation of substrates. Unlike, Fenton reaction other strategies like electron transfer mechanism is exhibited by Co3O4 NPs due to their high redox potential. Co3O4 NPs are known for their peroxidase like activity in presence of substrates TMB (3,3',5,5'Tetramethylbenzidine) and OPD (o-Phenylenediamine). A platform

[72]

Fig. (7). Magnetic glassy carbon electrode modified with multi-layered nanocomposite Ag@MWCNT-IL-Fe3O 4 (Ag-Multiwalled carbon nanotube-Ionic Liquid-Fe3O4) as amperometric biosensor for glucose detection, adopted from ref [91].

using these NPs was developed to exhibit extrinsic peroxidase like activity to catalyze the oxidation of TMB and OPD by H2O2. Further, the biosensor was constructed for monitoring H2O2, and glucose at pH 7.4 and the limit of detection was found to be 0.015 mM and 0.005 mM, respectively [93]. In another study, hollow nickelpalladium NPs were developed possessing triple enzyme-like activity (catalase, oxidase and peroxidase). Based on the colorimetric method using TMB as a substrate, glucose was detected with a lower limit of 4.2 M [94]. Ni/Co Layered Double Hydroxides (LDHs) having intrinsic peroxidase like activity were designed for the detection of bio-



9

Fig. (8). Fe3O 4-Au based magnetic immunosensor for detection of -fetoprotein through electrochemiluminescene, adopted from ref [92].

molecules. Results showed a novel one-step method for detecting glucose and acetylcholine (Ach) at neutral pH. Glucose Oxidase (GOx) was used for sensing glucose and for Ach detection, acetylcholinesterase (AChE) and Choline Oxidase (ChOx) were used for generation of H2O2. The limit of detection was found to be 0.1 M and 1.62 M for glucose and Ach respectively [95]. Similarly, citrate coated Fe3O4 NPs exhibiting peroxidase-like activity in the presence of ATP at physiological pH were demonstrated. In this work, the enzyme like activity of MNPs was used to detect glucose with a colorimetric sensing limit of 50 M in a single step at pH 7.4. Further, this strategy was also extended to detect glucose in human serum within 5 min [77]. Mesoporous spheres of NiCo2O4 NPs displaying intrinsic oxidase and peroxidase activity were also reported. Results suggested that NPs can oxidise TMB directly without any participation of 1O2 and OH·. However, the peroxidase activity was stemmed from the oxidation of TMB in presence of both 1O2 and OH· species. Furthermore, the authors applied this enzymatic activity for glucose sensing with a detection limit of 1.6 M [96]. Other biomolecules of interest such as glutathione, dopamine and nucleic acids have also been detected by enzyme-mimetic activities of MNPs. Co3O4 nanotubes with triple enzyme mimetic activity (catalase, oxidase and peroxidase) were used to develop a colorimetric sensor for glutathione (GSH) with a sensing limit of 0.033 M [97]. TMB oxidation, in this case, occurred in the absence of H2O2 and in presence of Co3O4 nanotubes to produce blue coloured product. Reports revealed that in presence of DNA scaffold the peroxidase activity of Pt NPs can be shielded. This principle was used to design a paper based analytical device (PAD) for colorimetric detection and quantification of DNA. A linear response was observed with the concentration of DNA ranging from 0.0075 μM to 0.25 μM [98] (Fig. 9). An electrode sensor with -Fe2O3 (hematite) NPs was fabricated for detection of dopamine (DA). Electrochemical performance of -Fe2O3-modified glassy carbon electrode (GC/-Fe2O3) was elucidated using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Electro catalytic DA oxidation in phosphate buffer solution (6.8 pH) could be monitored with a detection limit of 236 nM [99]. The nanosensors described above relied mostly on the reactive properties of MNPs and do not utilize the magnetic properties of

Fig. (9). Schematic explaining, simple and rapid colorimetric detection of nucleic acids through a paper based analytical device (PAD), adopted from ref [98].

MNPs during the design of the sensors. The magnetic properties of MNPs prove an edge over other nanoparticles in the fabrication of sensors where the immobilization of nanoparticles at a site or flow of nanoparticles can be controlled using the magnetic field. A disposable sensing platform for the detection of salivary cortisol with a detection limit of 10 pM was reported, which uses the magnetic properties of MNPs. This device comprised an ink-based printed electrode (metalloporphyrin based macrocyclic catalyst) which can electrochemically reduce the salivary cortisol collected by MNPs conjugated aptamer. The disposable sensor contained a magnetic disc to direct the cortisol collected by MNPs towards the sensing electrode. A selectivity assay was performed by analysing four closely related steroids (progesterone, triamcinolone, corticosterone and cortisone) and it was found that the sensor was highly selective for salivary cortisol. Finally, the device was able to detect the variations of salivary cortisol in different obstructive sleep apnea patients [100] (Fig. 10) (Table 3). 4. ROLE OF MNPS IN NANOMEDICINE Theranostic agents are produced by combining the capabilities of diagnostics and therapeutic agents to facilitate the diagnosis and treatment in a single platform. MNPs with their characteristic magnetic properties and ability to have compatible biological


Vallabani et al.

Fig. (10). (a) Schematic of the disposable printed sensor enclosed in a plastic lamination with openings for contact pads and sensing area. A magnetic disc (r = 3 mm; t = 5 mm) is aligned and laminated at the back of the working electrode of the sensor (b) photograph of the sensor (c) The MNP/aptamer/cortisol complex is populated at the sensing electrode via magnetic enrichment where the reduction of cortisol occurs. Reprinted with permission from ref [100] Copyright (2017) Springer Nature.

Table 3.

Use of MNPs in bio-sensing and detection of biomolecules.


Size (nm)

Biomolecule


References

Fe3O4 NPs

13 ± 3.5

Glucose

Peroxidase like activity of Fe3O4 NPs was used to measure glucose with a colorimetric sensing limit of 50 M in a single step at pH 7.4.

[77]

Co3O4 NPs

8.3 ± 0.7

Glucose and H2O2

Peroxidase like activity was used for detection of H2O2 and glucose.

[93]

Limit of detection 0.015mM and 0.005 mM for H2O 2 and glucose respectively.

Nickel-palladium NPs

40

Glucose

Triple enzyme like activity (catalase, oxidase and peroxidase) was used in detection of glucose (LOD 4.2 M).

[94]

Ni/Co layered double hydroxides (LDHs) nanozymes

470

Glucose

Glucose and acetylcholine were detected with a limit of 0.1 M and 1.62 M respectively.

[95]

NiCo2O4 NPs

-

Glucose

Intrinsic oxidase and peroxidase activity used in glucose sensing (detection limit of 1.6 M).

[96]

Co3O4 nanotubes

100-200

Glutathione (GSH)

Triple enzyme mimetic activity (catalase, oxidase and peroxidase) was utilised to develop a colorimetric sensor for glutathione (GSH) detection with a sensing limit of 0.033 M.

[97]

Pt NPs

~5

Nucleic acids

A paper based analytical device (PAD) for the colorimetric detection and quantification of DNA (ranging from 0.0075 μM to 0.25 μM).

[98]

(DNA) -Fe2O3 (hematite) NPs

45

Dopamine

Can be used as an electrode sensor for detection of dopamine with a detection limit of 236 nM.

[99]

Aptamer-sensor aided by MNPs

1- 40

Salivary cortisol

Disposable sensing platform for the detection of salivary cortisol with a detection limit of 10 pM.

[100]

interaction at the cellular and molecular level enhanced their applications in drug delivery, targeting and imaging [8, 101-105]. For effective diagnosis and treatment, conjugation of multifunctional MNPs with targeting molecules or drugs allows simultaneous localization, early detection and treatment of tumors or diseases [23, 106-109]. Chemotheraphy is an efficient method to treat cancer cells, but its role in supressing tumours without side effects is a challenging task [110]. Natural products like curcumin possessing anti-cancer

properties can be used as an alternative to avoid the side effects of harmful drugs [111]. IONPs formulation containing a coating of cyclodextrin and pluronic polymer (F68) with curcumin loading efficiency (MNP-CUR) was studied. Results demonstrated that this formulation increased ROS (Reactive Oxygen Species) generation and caused mitochondrial membrane potential loss in MDA-MB231 (Breast cancer cells). Further, MNP-CUR exhibited efficient MRI, targeting characteristics along with their potent anticancer activity compared to bare NPs [112].


Cancer targeting through functionalization with antibodies or ligands on NPs allows the localization of apoptotic peptides, imaging dyes, silencing genes and chemotherapeutic agents at the tumour sites [19, 113]. Unlike non-specific or conventional methods (where the concentration of drug decreases in reaching the target), targeting with NPs maintains the drug concentration at tumour site and minimizes their effects on healthy cells or tissues. Additionally, the type of coating and charge on NPs surface also decides the particle distribution or localization in different organs. In one such report citrate stabilized IONPs were coated with different materials like carboxymethyl dextran, polyethylene glycolpolyethylene imine (PEG-PEI), methoxy-PEG-phosphate + rutin or dextran were studied to know their distribution in organs. Other than PEG-PEI coating, rest all NPs showed negative zeta potential at pH 7.4. In vivo results indicated after 48 hrs of intravenous injection, the NPs with negative potential were highly deposited in liver and spleen but PEG-PEI coated NPs accumulated in lungs. Thus, the study provided preliminary data that size and coating on IONPs surface can play a vital role in targeting specific organs for theranostics [114]. Related to targeting studies, IONPs were tagged with antiCD44 antibody (CD44 gets overexpressed in a variety of cancer cells), gemcitabine drug and results showed functionalized MNPs bound specifically to over expressed CD44 breast and pancreatic cancer cells. Moreover improved anti-tumour efficiency of conjugated MNPs (with drug and antiCD44 antibody) was observed compared to free drug and non-targeted MNPs [115]. In another study Interleukin-1 receptor antagonist was conjugated to SPIONs (SPION– IL-1Ra) to find its anti-edemal effect and applications in MRI imaging. In vivo studies in rats with C6 glioma revealed the administration of SPION–IL-1Ra significantly reduced the peritumoral edema and increased the life span by two-fold compared to controls. Moreover, the so developed nano conjugate had the characteristics of negative contrast and the particle retention in tumour allowed capturing T2 weighted MRI images [116]. Further, Mn doped ZnS NPs coated with paclitaxel loaded cell penetrating peptide (CPP) was studied for anticancer efficiency. Different peptides like penetration (PEN), R9 and pVEC were conjugated for enhancing the anticancer efficiency of NPs. In vitro data showed paclitaxel- R9 conjugated NPs were found to be more cytotoxic towards cancer cells (SKOV-3 and HeLa) with increased apoptosis. Further, in vivo studies were carried in breast cancer model and same R9 combination exhibited maximum localization in the tumour region and thus enhanced anti-tumour efficacy [117]. In order to improve the efficacy of cancer diagnosis and treatment, combinational therapy was used to provide a single multifunctional nano platform for imaging, targeted drug delivery and hyperthermia etc. [118-121]. Hyperthermia is a process in which the localised temperature is raised to 40-45oC to kill the cancerous cells using NPs encapsulated drugs accumulated near the tumour region. In a similar fashion MNPs generate heat in presence of an alternate magnetic field through magnetic moment oscillations (called magnetic hyperthermia) to damage tumour cells. Hydroxyapatite layered iron oxide NPs (IO-HAp) were prepared for cancer therapy following hyperthermia. In vitro results revealed an effective hyperthermia effect in MG-63 (osteosarcoma cells). The temperature was raised to ~45oC within 3 min and killed all the cancerous cells in an exposure of 30 min [122]. In another study polydopamine coated MNPs conjugated with mono-6-thio--cyclodextrin (Fe3O4@PDA@SH--CD) were synthesised and later loaded with doxorubicin (DOX). Data indicated DOX-loaded NPs were internalized in liver cancer cells and exhibited photothermal activity with near infra-red (NIR) irradiation (photothermal therapy is the generation of heat via infra-red exposure). Thus, explaining NPs synergistic role as chemo and photothermal agent in treating liver cancer. Furthermore, the multimodal NPs showed improved T2 contrast for MRI imaging [123].


11

Doping of IONPs with cobalt showed enhanced magnetic property with 20-30 times higher magnetic crystalline anisotropy compared to SPIONs. Based on these enhanced magnetic properties and large anisotropy, a nanohybrid of cobalt ferrite kernel as a core and Au as multi layered stratum (CoFe2O4@Au core-shell) possessing multiple applications in a single frame was designed. The synthesised nanohybrid was conjugated with DOX and the drug release profile was demonstrated at 5.4 pH equivalent to endosomal pH in cells. In vitro results showed that the DOX-NPs exposure to microwave irradiation in Hep2 cells exhibited enhanced mortality rate in comparison to nondrug conjugated NPs revealing the synergistic effect of hyperthermia and chemotheraphy. Further, the nanohybrid displayed an efficient T2 contrast for MRI imaging in both L6 and Hep2 cells [124] (Fig. 11). Polydiallyldimethylammonium chloride coated Pt NPs were shown to have broad light absorption properties in ultra-violet, visible and NIR (650-1200 nm) and can be used for extended PTT applications. These porous Pt NPs exhibited biocompatibility and their uptake occurred through the endocytic pathway in cells. Photothermal ablation using laser irradiation (8.4 W cm2) at 808 nm indicated 70% cell death within 3 min, thus explaining their better photothermal role for cancer treatment [125]. In general, hypoxia condition in tumours restricts the formation of reactive oxygen species and enhances the malignancy of bladder cancer cells [126]. As a novel strategy, additional O2 can be supplied by using O2-generating NPs like MnO2 to overcome hypoxia and generate ROS for killing cancer cells. A study revealed human serum albumin (HSA) coated MnO2-Ce6 NPs (HSA-MnO2-Ce6 NPs), due to their high reactivity towards H2O2 to produce O2, can be used to treat bladder cancers. In vitro study showed the generation of O2 was increased by two-fold in presence of H2O2 under laser irradiation (660 nm) and enhanced photodynamic therapy (use of light to produce singlet oxygen from O2 to kill tumour cells) effect was observed on bladder cancer cells. In addition, in vivo data demonstrated NPs potential role in treating bladder cancer via photodynamic ablation [127]. Furthermore, MNPs were applied to develop new strategies to mitigate infections caused by several bacteria and to treat multiple drug resistance or to eradicate biofilms. Core shell MNPs in combination with human antibacterial peptide cathelicidin LL-37, synthetic ceragenins CSA-13, CSA131, and antibiotics like colistin, vancomycin were reported to destroy the methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. The combination exhibited potent antibacterial properties and can overcome bacterial drug resistance [128]. In a related study, multiple drug resistant Staphylococcus aureus and Escherichia coli were trapped by positively charged MNPs (core shell Fe3O4@SiO2-NH2 NPs) and completely killed within 30 min after exposure to radiofrequency. In addition, the strategy was found to kill the bacteria without leading to antibiotic resistance [129]. Further, nanocarrier containing SPIONs and antibiotic methicillin was also shown to avoid the biofilm formation by Staphylococcus epidermidis. The NPs penetrated 20 M thick biofilms in presence of an external magnetic field and complete eradication occurred at SPION 40 μg/mL and methicillin 20 μg/mL concentrations [130]. To inhibit oral bacteria (Streptococcus mutans) biofilms, Pt NPs were applied and succeeded in preventing the biofilm growth [131]. In addition, a study screened 20 potent biofilm forming Pseudomonas aeruginosa and exposed them to IONPs. Results indicated that at a concentration of 30 μg/mL, IONPs reduced the biofilm biomass in most of the isolates. However, for few stains, it stimulated biofilm formation due to iron source [132]. Similarly, Ni NPs can be used to prevent or eradicate biofilm produced by Burkholderia Cepacia [133]. Hence, MNPs with overarching antimicrobial activity can be used to kill bacterial biofilms and can also overcome their multiple drug resistance ability compared to antibiotics (Table 4).


Vallabani et al.

Fig. (11). Synthesised CoFe2O4 @Au core shell for applications in MRI, hyperthermia and drug delivery. Reprinted with permission from ref [124] Copyright (2016) Springer Nature.

Table 4.

List of MNPs used for applications in nanomedicine. Nanoparticle/ Material

Size (nm)


References

IONPs with curcumin

~9

Targeting characteristics along with their potent anticancer activity.

[112]

IONPs and tagged with anti-CD44 antibody and gemcitabine

63

For targeting CD44 breast and pancreatic cancer cells.

[115]

SPION–IL-1Ra

43.1

Significantly reduced the peritumoral edema in rats and showed negative contrast for capturing T2 weighted MRI images.

[116]

ZnS NPs with paclitaxel loaded cell penetrating peptide

100 – 150

Found to be more cytotoxic towards cancer cells (SKOV-3 and HeLa) with increase in apoptosis.

[117]

In vivo studies in breast cancer model showed maximum NPs localization in tumour and enhanced anti-tumour efficacy. Hydroxyapatite layered iron oxide NPs (IO-HAp)

62.14 ± 10.8

For effective hyperthermia effect in MG-63 (osteosarcoma cells).

[122]

MNPs with DOX Fe3O4 @PDA@SH--CD

8-14

Acts as a synergistic chemo and photothermal agent in treating liver cancers.

[123]

CoFe2O4 @Au core-shell with DOX

11-14

Have synergistic hyperthermia and chemotheraphy effect along with T2 contrast MRI imaging efficiency.

[124]

Porous Pt NPs

72 ± 18

Can be used as a photothermal agent for cancer treatment.

[125]

Human serum albumin coated MnO2-Ce6 NPs

118.6 ± 8.1

Therapeutic efficacy for bladder cancer via photodynamic ablation.

[127]

Core shell MNPs with human antibacterial peptides

11 - 13

Possessed antibacterial properties against methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

[128]

Fe3O4 @SiO2-NH 2

10 -15

Antibacterial property against Staphylococcus aureus and Escherichia coli.

[129]

SPIONs with antibiotic methicillin

83 ± 6

Avoided biofilm formation by Staphylococcus epidermidis.

[130]

Pt NPs

3.7 ± 2.7

Inhibits oral bacteria (Streptococcus mutans) biofilm.

[131]


CONCLUSION AND FUTURE PERSPECTIVE In summary, MNPs with a broad range of applications are being used extensively in imaging, bio-sensing, therapeutic and theranostics. Synthesis of functionalized MNPs, doped hybrids, multifunctional materials for applications in advanced imaging modalities like MRI/PET and PET/CT are pushing the limits of science and engineering for creating a better understanding of cancers and diseases. These novel nanohybrids have demonstrated efficient imaging, targeting and chemotherapeutic efficacy and have the potential to be combined on a single platform. Unique properties of MNPs including low toxicity, high colloidal stability, magnetic behaviour and easy functionalization have given them an added advantage in comparison to other materials which are currently in clinical practice. The FDA approval of ferumoxytol, GastroMARK, Feridex has provided the much-needed impetus to MNP based products in clinical trials. Currently, most of the approved MNP formulations are used to treat anaemia patients with chronic kidney diseases and as imaging agents in clinical trials. These limitations are due to lack of knowledge with new nano contrast agents compared to conventional contrast agents. Considering these lacunae there is a lot of scope for development of a library of novel MNP hybrids with improved physicochemical properties, low toxicity and better kinetic parameters. Thus, complete information on MNPs for radiologists and physicians can help to increase clinical outcome and their novel products can withstand the consumer market for a long time. CONSENT FOR PUBLICATION Not applicable. CONFLICT OF INTEREST The authors declare no conflict of interest, financial or otherwise. ACKNOWLEDGEMENTS The financial assistance for the Centre for Nanotechnology Research and Applications (CENTRA) by The Gujarat Institute for Chemical Technology (GICT) and the funding from the Department of Science and Technology-Science and Engineering Research Board (SERB) (Grant No.: ILS/SERB/2015-16/01) to Dr Sanjay Singh under the scheme of Start-Up Research Grant (Young Scientists)- Life Sciences are gratefully acknowledged. Sanjay Singh thanks the Union for International Cancer Control (UICC) for Yamagiwa-Yoshida (YY) Memorial International Cancer Study Grant, and also thankful for the financial support provided by the Ahmedabad University as Seed Grant (AU/SG/SAS/DBLS/1718/03). The Early Career Research Grant Award (ECRA) to Dr. Ajay S. Karakoti) Grant No. ECR/2016/000055) is also gratefully acknowledged.

Current Drug Metabolism, 2018, Vol. 19, No. 00 [7]

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[10]

[11]

[12]

[13]

[14]

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[20]

[21] [22] [23] [24]

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