Biomedical Applications of Magnetic Nanomaterials

Chapter 12

Biomedical Applications of Magnetic Nanomaterials Anupam Guleria, Kalpana Priyatharchini and Dinesh Kumar Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India

12.1 INTRODUCTION Recent advances in nanotechnology and biotechnology have focused on the development of multifunctional nanoparticles as representative nanomedicines, with multimodal capability and therapeutic functionality for simultaneous biomedical imaging and therapy. Such all-in-one nanosystem probes have emerged as fascinating possibilities to overcome the vaults of traditional diagnosis and therapy, through optimized therapy called “personalized medicine,” due to their unique characteristics such as multifunctionality, large surface area, structural diversity, and long blood circulation time [1,2]. Diverse types of nanoparticles in development include liposomes, drug conjugates and complexes, micelles, dendrimers, vesicles, core-shell particles, microbubbles, carbon nanotube and quantum dots [3]. Among these nanoparticles, magnetic nanoparticles (MNPs) of sizes ranging from 1 to 100 nm, exhibit interesting and considerably different magnetic properties compared to their bulk counterparts, mainly due to finite size effects. Owing to their unique magnetic properties, such as superparamagnetism, high field irreversibility, high saturation field, extra anisotropy contributions that can further be manipulated by an external magnetic field gradient, and ability to conjugate with many biological and drug entities (such as biocompatible polymers, antibodies, ligands, and proteins), MNPs offer a wide variety of applications in biomedicine: contrast agents in magnetic resonance imaging (MRI) [4–7], site specific magnetic targeting [8], magnetic hyperthermia treatment [9–11], multimodal imaging [12], magnetic field-dependent controlled drug delivery [13–15], magnetofection [16–18], biomedical separation [19,20], tissue repair [21–23], etc. Further, due to their small size, these NPs do not present any extravasations from normal vessels and get accumulated at the pathological sites, such as tumors, via the enhanced permeability and retention (EPR) effect. A schematic illustration of various biomedical applications of magnetic nanomaterials is shown in Fig. 12.1. Applications of Nanomaterials. https://doi.org/10.1016/B978-0-08-101971-9.00013-2 Copyright © 2018 Elsevier Ltd. All rights reserved.

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346 Applications of Nanomaterials

nd

liga tor n cep Re ractio inte

Hi

gh

gr ad

ien

tm

ag

ne

t

se

a d fiel g rele tic u gne led dr a M trol con

Imaging

Targeting

Drug delivery

Diagnosis

Tumor tissue

tio

n

Drug

Magnetic hyperthermia

He

at

ge ne ra

s

DNA

of MNP ns

Magnetofection

Targeting ligand

icat ppl io

Bi

edical A om

Multimodal imaging

Cells

Alternating current Magnetic field

pe

to

so oi

i

d Ra

PET, SPECT

Optical tag

Ps

MN

Visible, near infrared, fluorescence imaging

FIG. 12.1 Schematic illustration of biomedical applications of magnetic nanomaterials.

Different types of MNPs have been evaluated for biomedical applications mainly by exploiting nanoscale magnetic properties, such as enhanced magnetic moments and superparamagnetism [14]. Because most of the above-mentioned applications require well-defined and controllable interactions between the MNPs and living cells, tremendous progress is continually being made in nanotechnology towards engineering the critical features of nanoparticles, such as composition, size, morphology and surface chemistry, to ameliorate the magnetic properties and influence the bio-applications of the designed MNPs in vivo [24,25]. Generally, a biomedical MNP is comprised of an inorganic nanoparticle core with a biocompatible surface coating to provide stabilization under physiological conditions and conjugated with functional ligands. The nanoparticle core is made up of materials with high saturation magnetization at room temperature, such as transition metals (e.g., Fe, Co, Ni, Mn), metal oxides (e.g., Fe3O4, γ-Fe2O3), and rare earth elements such as Gd (e.g., chelated organic gadolinium complexes) [6]. Among the various types of MNPs, Iron oxide nanoparticles such as magnetite (Fe3O4) are the most commonly

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employed nanoparticles for biomedical applications due to their remarkable magnetic properties, chemical stability, biocompatibility [26] and relative ease to functionalize for a wide range of applications. Iron oxide nanoparticles with particle size <10 nm exhibit quantum size effects and larger surface areas, leading to a very interesting phenomenon known as superparamagnetism (i.e., NPs exhibit magnetism only in the presence of an external magnetic field that is lost once the external magnetic field is removed) and thus have improved dispersive properties in the absence of magnetic field, and later are directed to a defined location in the presence of a magnetic field or heated in the presence of an externally applied AC magnetic field [27]. Iron oxide NPs also have very good biocompatibility as they are metabolized in the hepato-renal system and enter endogenous iron reserves via hematopoiesis [24]. In parallel with iron oxide NPs, other NPs that have gained attention recently are those based on Gd and Mn-containing inorganic nanocrystals, such as Gd2O3 [28,29], NaGdF4 [30], and MnO [31], due to their large magnetic moment, and are preferred for contrast enhancement in MRIs owing to their tremendous paramagnetic properties. However, when dealing with biological systems, the MNPs should be highly biocompatible and should have low aggregation or toxic effects. Therefore, MNPs are further coated with a wide variety of materials, such as hydrophilic natural and synthetic polymers and amphiphilic molecules, to prevent particle aggregation, maintain aqueous stability, and biocompatibility [32,33]. Various functionalities can then be conjugated onto the surface of MNPs including bio-vectors (such as peptides, aptamers or antibodies for their ability to guide the movement of MNPs in a living subject and to accumulate them in areas of interest, like tumors), imaging motifs, dyes, or therapeutic agents to serve as workhorses for multimodality imaging (e.g., MRI, nuclear and optical imaging and/or for therapy) [34]. The preclinical and clinical studies have proven some nanoscale formulations to be safe and have further been approved by the Food and Drug Administration (FDA) for clinical use, with more in clinical trials for approval. For example, commercial products like Resovist, Endorem, Sinerem, or Combidex, which consist of carbohydrate-polymer (dextran) coated magnetite and maghemite nanoparticles diluted in water [35]. These superparamagnetic iron oxide nanoparticles (SPIOs) coated with organic molecules are used as MRI contrast agents for detecting pathological alterations in several organs, for instance the liver, spleen, lymph nodes, or brain [7,35–37]. Furthermore, due to their specific adsorption they could possibly be helping physicians to identify dangerous arteriosclerotic plaques by MRI [38]. Numerous studies have explored the potential of such MNPs as therapeutic and diagnostic agents for the management of diseases such as cancers and cardiovascular diseases. This chapter gives an overview of the recent developments and biomedical applications of multifunctional MNPs as well as research activities in progress related to this arena.

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12.2 MAGNETIC NANOPARTICLES AS MRI CONTRAST AGENTS 12.2.1 Introduction to MRI Contrast Agents MRI has become one of the most widely used and powerful noninvasive imaging modalities, gaining particular interest due its ability to monitor anatomical changes accompanied with any physiologic and molecular changes. It provides high-quality three-dimensional images with an eminent degree of soft tissue contrast and high spatial resolution. The image viability and/or intrinsic tissue contrast in MR images is determined by the longitudinal (T1) and transverse relaxation times (T2) of water protons in human bodies [39]. Longitudinal relaxation time T1, also known as the spin-lattice relaxation time, is the time constant of the exponential recovery of magnetization to its original alignment with the magnetic field after a perturbation is applied to the system. Protons that relax rapidly (short T1) recover full magnetization along the longitudinal axis quickly and produce high signal intensities. For the protons which relax more slowly (long T1), full magnetization along the longitudinal axis is not recovered before subsequent RF pulses, and so they inherently produce a lower intensity signal [39]. The transverse relaxation times T2 referred to as the spin-spin relaxation time is the time constant of the exponential decay of the magnetization in the plane perpendicular to the static magnetic field [transverse magnetization (Mxy)] after an RF pulse. Usually during an RF pulse, proton nuclei spin in phase with each other, whereas after the pulse, the magnetic fields of all the nuclei interact with each other, exchanging energy between them. As a consequence, the protons lose their phase coherence and tend to spin in a random fashion, eventually resulting in a net magnetic moment of zero in the xy plane [40]. Fig. 12.2A shows a pictorial demonstration of the basic principles of T1 and T2 relaxation processes in MR imaging. Under an external magnetic field (B0) (along the z-axis of MR scanner), the water protons align their spins in the direction of B0 producing a net magnetization Mz(0) in the same direction. Upon the application of 90° RF pulse, the net magnetization gets flipped to the xy plane generating transverse magnetization (Mxy) and the net longitudinal magnetization (Mz) is zero. The exponential recovery and decay of longitudinal and transverse magnetization, respectively, as a function of time is shown in Fig. 12.2B, for pure water and an aqueous sample solution of gadolinium oxide magnetic nanoparticles synthesized by our group. An anatomical image of healthy tissues with exquisite spatial resolution can be obtained using MRI due to significant differences in the relaxation times T1 and T2 of these tissues, however, many pathological conditions do not lead to significant morphological changes and thus show only small differences in native relaxation times. In such instances, a diagnosis based purely on the resulting images may not be accurate, and so for better lesion visualization and vascular characterization, the imaging sensitivity can be enhanced through the administration of MRI contrast agents prior to scanning. MR contrast agents

z

z

B0

Mz(0)

z

z

x

10 0

4000

30

60 90 120 150 Echo time (TE, ms)

180

70

r2 = 35.4 mM−1s−1

60 50

4

40 30

0.25

1/T (s−1)

6

20 2 10 0

0 0.0

1.6

0.0

0.4 0.8 1.2 Gd concentration (mM)

1.6

(D)

349

FIG. 12.2 (A) Schematic representation of T1 and T2 relaxation processes, (B) exponential recovery and decay of longitudinal and transverse magnetization, respectively, as a function of time for aqueous sample solution of gadolinium oxide magnetic nanoparticles and pure water, (C) plots of 1/T1 and 1/T2 inverse relaxation times of gadolinium oxide MNPs as a function of Gd concentration, and (D) R1 and R2 map images of MRI sample solution of gadolinium oxide nanoparticles as a function of Gd concentration.

12

0.4 0.8 1.2 Gd concentration (mM)

20

r1 = 4.67 mM−1s−1

8

10

3000 1000 2000 Inversion time (TI, ms)

6

tion)

0 0

8

1.75

le solu

2

−2000

samp

4

d2 O

1.50

ms (G

3

500

0

T

~2 1

T2 ~33

(Water)

1.25

−1000

1000

(W

10

R2 map

1.00

Mtrans

Mz

r)

ate

R1 map

0.75

T2~970 ms

1500

s 0m

x

0.50

T1~195 ms (Gd2O3 sample solution)

0

x

Mx y = M0e−t/T2

2000

y

50

x

y

40

x

y Exponential Mxy decay

60

y

0.00

x

1000

(C)

Mz(0)

30

y

Gd concentration (mM)

RF

pu

lse

y

Mz = M0(1-e−t/T1)

2000

1/T (s−1)

z

90°

3000

(B)

z

Biomedical Applications of Magnetic Nanomaterials Chapter

(A)

Exponential Mz recovery

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(MR-CAs) are compounds that highlight areas of abnormality via passive accumulation at the region of interest and interact with surrounding water protons by shortening their relaxation times, which in turn improves the sensitivity of MRI by enhancing the contrast in that region, with brighter signals in T1 images or darker signals in T2 images [6,41]. A number of MR-CAs have been developed and research continues in order to find new and more selective contrast media for better delineation of diseases and thus providing radiologists with better image guidance to make a precise and timely diagnosis. Generally, contrast agents with paramagnetic or superparamagnetic properties are used to shorten the T1 and T2 relaxation times and accordingly are classified as T1 and T2 contrast agents, and their ability is referred to as relaxivity r1 and r2, respectively. To be an effective T1 MR contrast agent, a high r1 and a low r2/r1 ratio are mandatory, while T2 MRI contrast agents need to have a high r2 value. T1 contrast agents increase the signal intensity and thus provide positive contrast enhancement in T1 weighted images, whereas T2 contrast agents decrease the signal intensity resulting in negative contrast enhancement in T2 weighted images. Currently, clinically available MRI contrast agents are paramagnetic complexes, usually gadolinium (Gd3+) chelates [42], which includes Gd-DTPA (gadolinium diethylenetriaminepentaacetic acid, Magnevist; Schering AG), ProHance, Omniscan, Optimark, Dotarem, Gadovist, and Vasovist [43]. However, these gadolinium complexes have several disadvantages in clinical settings, such as inefficient contrast enhancement due to low relaxivity, short circulation times due to their rapid excretion through urine, the lack of drug specificity towards a diseased site, the necessity of a large dose to achieve high local contrast, high toxicity, and other adverse side effects inducing nephrogenic system fibrosis (NSF) due to high drug doses [44]. To overcome the above-mentioned drawbacks of Gd-chelates based MR-CAs, magnetic nanoparticle based T1 and T2 contrast agents have been intensively developed in recent years. We describe below the MNP-based T1, T2 and T1 & T2 dualmodality contrast agents with examples and provide a brief overview of the currently clinically available MR-CAs and CAs undergoing clinical evaluation.

12.2.2 Magnetic Nanoparticle Based T1 MRI Contrast Agents Magnetic nanoparticles are expected to have a better ability for T1 contrast enhancement due to better interaction with water protons with large surface area, increased payloads of paramagnetic metal ions on the surface, and longer life-time in the body [45]. The most evident candidates for nanoparticulate T1 contrast agents are systems with a large number of unpaired electrons, such as those containing Gd3+, Mn2+, and Fe3+ ions. Among those, gadolinium-based nanoparticles (GdBNs) have been explored most rigorously as gadolinium complexes are already used as clinical contrast agents. Small size GdBNs offer more Gd3+ ions at the surface for water hydration than large particles due to high surface to volume ratio and thus have high relaxivity r1. To date, a large number of

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GdBNs have been investigated as T1 contrast agents including Gd2O3 [28,29,46,47], Gd2O(CO3)2
H2O [48], GdF3 [49], NaGdF4 [30,50], and KGdF4 [51], with Gd2O3 MNPs receiving the most investigation. Gd2O3 MNPs were first evaluated for their physicochemical and MR properties in 2003 by McDonald and colleagues [52], followed by another report, in which these MNPs with diameters between 20 and 40 nm were reported to possess relaxivities comparable to Gd-DTPA chelates [53]. Furthermore, ultrasmall nanoparticle Gd2O3 of diameter between 3 and 10 nm has been reported to exhibit twice the relaxivity of Gd-DTPA [29]. As shown in Fig. 12.2B, both T1 and T2 relaxation of water protons increases in the presence of Gd2O3 magnetic nanoparticles. The slopes obtained from plot of 1/T1 and 1/T2 versus Gd concentration represent the relaxivities r1 and r2, which comes out to be 4.67 and 35.4 mM 1 s 1, respectively (Fig. 12.2C). A dose-dependent contrast enhancement in relaxivities is clearly seen in the R1 and R2 map images for Gd2O3 magnetic nanoparticles, as shown in Fig. 12.2D. The capability of D-glucuronic acid coated ultrasmall Gd2O3 MNPs as a T1 MRI contrast agent has also been investigated in vivo in a rat with a brain tumor [28,47]. Fig. 12.3A shows a series of 1.5 T

FIG. 12.3 Applications of magnetic nanoparticles as T1 and T2 MRI contrast agents. (A) A series of 1.5 T in vivo T1 MR images of a brain tumor (indicated with an arrow) in a rat after intravenous injection of an aqueous sample solution of D-glucuronic acid coated Gd2O3 NPs into the rat tail vein. (B) MR images of a mice brain bearing tiny glioma before and after injection of folic acidconjugated MnO nanoparticles. (C) A series of 1.5 T in vivo T1 MR images of a mouse liver and kidney with time after injection of MnO nanocolloid into a mouse tail vein. (D) Use of extremely small-sized iron oxide nanoparticles for high-resolution blood pool T1 MR imaging. (E) A series of 3 T in vivo T2 MR images of kidneys and liver (labeled as “K” and “L”, respectively) before and after intravenous injection of a sample solution of D-glucuronic acid coated ultrasmall Dy2O3 nanoparticles into a mouse tail vein. ((A)–(D) Reproduced with permission from J.Y. Park, M.J. Baek, et al., ACS Nano 3 (2009) 3663–3669; N. Chen, C. Shao, et al., ACS Appl. Mater. Interfaces 6 (2014) 19850–19857; M.J. Baek, J.Y. Park, et al., ACS Appl. Mater. Interfaces 2 (2010) 2949–2955; B.H. Kim, N. Lee, et al., J. Am. Chem. Soc. 133 (2011) 12624–12631. Copyright © 2010, 2014, 2011, 2009, respectively, American Chemical Society. (E) Reproduced with permission from K. Kattel, J.Y. Park, et al., Biomaterials 33 (2012) 3254–3261.)

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in vivo T1 MR images of a brain tumor in a rat taken at different times demonstrating that D-glucuronic acid coated Gd2O3 MNPs work as T1 MR-CAs. It has further been shown that these MNPs were completely excreted from the body through the kidneys and bladder [47]. In another study by Liang et al., paramagnetic gadolinium hydrated carbonate nanoparticles with size 2.3 nm and r1 relaxivity of 34.8 s 1 mM 1 was synthesized. The reported r1 of these NPs is 9.4 times higher than that of Gd-DTPA at 0.55 T [54]. GdF3 [49], NaGdF4 [30], and GdPO4 [55] nanoparticles have also been investigated as T1 contrast agents with strong positive contrast effects and significantly small r2/r1 values. The r1 values for these nanoparticles are 7.4, 7.2 and 13.9 s 1 mM 1, respectively, which bodes well for MR imaging applications. Lately, manganese oxide (MnO) nanoparticles have been developed as T1 MRI contrast agents [31]. The merit of MnO NPs over GdBNPs is that Mn is much less toxic than Gd, is an essential element for many living systems, and plays important roles in many biological processes, and thus is preferred for biomedical applications. These NPs alleviate the acquisition of good quality T1-weighted MR images of the brain, liver, kidney, and spinal cord, demonstrating very fine anatomic structure in animal models [56]. Na et al. reported clear T1-weighted MR images with fine anatomic structures of the mouse brain after the intravenous injection of MnO NPs functionalized with Herceptin into the tail vein of rat, thus displaying their ability for the diagnosis of neurological diseases such as Alzheimer’s and Parkinson’s diseases where anatomic details with highly spatial resolution are required [31]. Similarly, Yu and colleagues reported Folic Acid-Conjugated MnO Nanoparticles as potential glioma-targeted T1 contrast agents, which give an enhanced contrast effect in the tiny glioma region with a prolonged imaging period as shown in Fig. 12.3B [57]. Furthermore, Baek et al. synthesized ultrasmall MnO nanoparticles (2 to 3 nm) conjugated with biocompatible D-glucuronic acid and demonstrated their potential for in vivo imaging of mouse livers and kidneys (Fig. 12.3C) [58]. Mn3O4 NPs were recently synthesized by Xiao et al., using a simple and green technique, and obtained an ultrahigh relaxivity of 8.26 mM 1 s 1 which is the highest value reported to date for Mn-based NPs [59]. Despite all of these advances in Gd- and Mn-based NPs agents, the issue of accumulative toxicity still persists and limits their clinical applications [60–62]. Iron oxide is more biocompatible than Gd- or Mn-based materials because the iron species, which are mostly stored as ferritin in the body, are rich in human blood [63]. However, common iron oxide nanoparticles are not appropriate for T1 MRI contrast agents due to their large r2/r1 ratio, although their r1 is often higher compared to Gd-chelates. This problem can be resolved by decreasing size of these MNPs and small-size iron oxide NPs have been reported as a potential candidate for T1 contrast agents because the r2/r1 ratio of iron oxide NPs rapidly decreases with decreases in size and these NPs can enhance the T1 effect

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by their large surface area and suppress the T2 effect by their small magnetic moment [64]. It has been shown that ultrasmall particles of iron oxide can be utilized as T1 contrast agents. The ability of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) to act as positive contrast enhancers was first reported by Chambon et al. in 1993 [65]. Since that time, other studies have also shown the capability of USPIOs as a positive contrast agent for magnetic resonance molecular imaging [63,64,66]. The use of ultrasmall particles of iron oxides has also been explored to develop blood pool contrast media for magnetic resonance angiography [63,67]. Fig. 12.3D shows in vivo high-resolution blood pool MR imaging using ultrasmall iron oxide nanoparticles with a diameter of 3 nm, which enabled the clear observation of various blood vessels with sizes down to 0.2 mm [63].

12.2.3 Magnetic Nanoparticle Based T2 MRI Contrast Agents To generate strong T2 contrast effects, MNPs should have large magnetization, such that when placed in an external magnetic field, the NPs get magnetized and in turn generate induced magnetic fields. These induced magnetic fields perturb the spin-spin relaxation (T2) processes of water protons in the vicinity, giving rise to dark (negative) MRI images. The most popular material studied for T2 contrast agents is iron oxide NPs (magnetite and maghemite) due to their chemical stability, lack of toxicity, and biodegradability. These NPs have the ability to dramatically shorten T2* relaxation times in the liver, spleen, and bone marrow by selective uptake and accumulation in the cells of the reticuloendothelial system (RES) [68,69]. Because the biological distribution of the NPs is directly dependent on their size, iron oxide particles of different sizes have been developed for clinical applications on MR imaging. These MNPs are broadly classified according to their size as micrometer-sized paramagnetic iron oxide (MPIO) with particle size in micrometer range, superparamagnetic iron oxide (SPIO) particles with particle size >50 nm, or ultrasmall SPIO (USPIO) particles with particle size smaller than 50 nm [69]. SPIOs with diameter > 50 nm have been clinically used for the diagnosis of liver diseases because when injected intravenously they are selectively taken up by the Kupffer cells of the liver. Generally, the hepatic diseases, such as a liver tumor or liver metastasis, destruct the normal liver architecture leading to a lack of Kupffer cells in that region. Therefore, due to the negligible uptake by the abnormal liver, the SPIO presents a strong contrast between normal and abnormal tissues, enabling clear detection of the abnormal tissue. Examples of SPIOs include ferumoxides (Endorem) and ferucarbotran (Resovist), which are commercially available on the European market for intravenous use [69,70]. Endorem has an iron oxide core of diameter 4–6 nm embedded inside a dextran coating and Resovist has an iron oxide core of 4.3 nm and is coated with carbodextran to a total diameter of 60 nm. While the SPIOs agents are mainly taken up in the liver, spleen,

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and bone marrow, USPIO agents have the ability to pass reticuloendothelial system (RES) and can be taken up in normal lymph nodes and thus have been applied for lymph node imaging [71,72]. One such compound, ferumoxtran10 (Sinerem, AMI 227, Laboratories Guerbet), is currently under development with applications for the diagnosis of inflammatory and degenerative disorders associated with high macrophage activity [71]. Other commercial USPIO products include ferumoxytol and Supravist (SHU-555C). Table 12.1 shows the list of iron oxide-based agents approved for clinical applications or clinically tested. SPIO NPs are also used to track stem cells transplanted into organs like the brain or to demonstrate macrophage activity within atherosclerotic plaque and the detection of such plaques by MRI [38,85]. There are, however, some drawbacks associated with iron oxide MNPbased contrast agents. The main drawback is that these CAs suffer from poor contrast and are interfered with by magnetic inhomogeneity or susceptibility artifacts, which lead to the intrinsic tissue signal void for in vivo imaging and thus may result in an incorrect interpretation of the T2 weighted MR images. For example, so that produced signal voids can be confused with signals from bleeding, calcification, or metal deposits [56]. Therefore, the search for more reliable contrast agents continues and several contrast agents with different compositions have been developed and tested for T2 contrast agents, such as FePt, FeCo alloy nanocrystals [86,87], and metaldoped iron oxide nanoparticles, including CoFe2O4, MnFe2O4, and NiFe2O4 [88–90]. Among them, the MnFe2O4 nanoparticles have been found to have a very high magnetization and large relaxivity values leading to shortening of T2 and thus have the strongest MR contrast effect in T2-weighted images [88,89]. However, the long term toxicity issues of these nanomaterials have yet to be assessed. The paramagnetic dysprosium (Dy3+) ion has also been proposed as an alternative for T2 CA in high field MRI because of its high magnetic moment (10.6 μB) and short electronic relaxation time (10 13 s) [91,92]. Therefore, dysprosium nanomaterials (nanoparticles and nanorods) have been developed as T2-based NPs contrast agents with improved magnetic and physicochemical properties [93,94]. For example, NaDyF4 NPs were investigated as T2 CAs with the potential to enhance T2 contrast at ultrahigh field such as 9.4 T, which is 10-fold higher than the clinically used T2 CA (such as Resovist) [94]. Other Dy3+-based (e.g., Dy2O3, Dy(OH)3) and Ho3+-based (Ho2O3) NPs have also been reported as T2-based CAs [93,95]. The potential of dysprosium oxide NPs as T2 contrast agent has been further investigated through in vivo MR imaging. D-Glucuronic acid coated dysprosium oxide NPs with a core diameter of 3.2 nm and r2 of 65.04 s 1 mM 1 were injected intravenously to the mouse tail vein and in vivo T2 MR imaging shows negative contrast enhancements in both the liver and kidneys of a mouse as shown in Fig. 12.3E [93,95].

TABLE 12.1 List of Magnetic Nanoparticle Based Agents Approved for Clinical Applications or Clinically Tested

Class

Ferumoxsil AMI-121

Oral SPIO

>300 nm

Ferristene OMP

Oral SPIO

3.5 m

Ferumoxides AMI-25

SPIO

80–150 nm

Ferucarbotran SHU-555A

SPIO

Ferumoxtran10, AMI-227, BMS-180549

USPIO

Coating agent Silica

Applications

Status

Trade and common names ®

References

Approved

Lumirem , Gastromark®, Ferumoxsil®

[73,74]

MRI contrast agent for bowel imaging

Approved

Abdoscan®, Ferristene®

[75]

Dextran T10

Liver imaging; cellular labeling

Approved

Feridex®, Endorem®, Ferumoxide®

[73]

62 nm

Carboxydextran

Liver imaging; cellular labeling

Phase III (USA), Approved (Japan, EU, Australia)

Resovist®

[76,77]

20–40 nm

Dextran T10

Metastatic lymph node and macrophage imaging; blood pool agents; cellular labeling

Phase III

Sinerem®, Combidex®, Ferumoxtran®

[73,78,79]

12

Gastrointestinal tract imaging

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Compound

Mean particle size

355

Continued

Compound

Class

Mean particle size

Coating agent

Applications

Status

Trade and common names ®

References

Ferumoxytol CODE 7228

USPIO

18–20 nm

Carboxymethyldextran

Macrophage imaging; blood pool agent; cellular labeling

Phase III

Feraheme (ferumoxytol)

[80]

Ferucarbotran SHU-555C

USPIO

3–5 nm

Carboxydextran

Blood pool agent; cellular labeling

Phase III

Supravist®

[81]

VSOP-C184

USPIO

4–8 nm

Citrate

Blood pool agent; cellular labeling

Phase I

Feruglose NC100150

USPIO

4–7 nm

PEGylated starch

Blood pool agent

Development discontinued

[82]

Clariscan®

[79,83,84]

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TABLE 12.1 List of Magnetic Nanoparticle Based Agents Approved for Clinical Applications or Clinically Tested—cont’d

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12.2.4 Magnetic Nanoparticle Based T1-T2 Dual-Mode MRI Contrast Agents As discussed in previous sections, T1 and T2 contrast agents are used in clinics to improve the sensitivity of MRI by increasing the contrast of the pathogenic tissue from the normal tissue. However, single mode (T1 or T2) contrast agents may not always be sufficient to provide highly accurate diagnostic information. Therefore, T1-T2 dual-mode contrast agents have been introduced for an improved diagnosis that could provide complementary diagnostic information over a single modality, instead of the combination of multiple imaging modalities, and with advantages such as no discrepancies in the penetration depths and spatial/time resolution of various imaging techniques [96]. Several studies have confirmed that the T1-T2 dual-modal contrast agents could improve tissue resolution on lesion detection [96,97]. Generally, all MR-CAs intrinsically show both T1 and T2 relaxation enhancement effects. For example, the SPIO NPs show a predominant T2 effect and decreasing their size leads to improvement of the T1 effect, but their T2 effects are reduced as well [64,66,68,69]. Furthermore, paramagnetic Ln3+-based MNPs (such as Gd3+ and Dy3+) have been extensively studied for their T1 and T2 effects, yet simultaneously achieving high r1 and r2 is very difficult. Therefore, the characteristics of T1-T2 dual-mode contrast agents can be achieved by exploiting the unique design concepts of nanoparticles like the association of regular T1 and T2 CAs [96]. For example, Lee and colleagues synthesized ultrasmall MnO-coated Gd2O3 nanoparticles (1–2 nm) as T1/T2 dual-contrast agents, with the r1 and r2 of 12.8 and 26.6 mM 1 s 1 at 3 T, respectively [98]. Dual-mode MR contrast agents consisting of SPIO NP cores with gadolinium ions introduced into the coating layer have also been synthesized and investigated. The obtained NPs have the r1 and r2 relaxivity values of 53.7 and 375.5 mM 1 s 1, respectively, at 15 MHz [99]. Yang and colleagues synthesized T1 and T2 dual-mode CAs by modifying Gd-chelates on the surface of magnetic iron oxide nanoparticles [100]. However, the main issue with such types of T1-T2 dual-mode CAs is that when T1 and T2 contrast materials are in direct contact, the magnetic field induced by the T2 contrast material may affect the electronic spins of paramagnetic T1 contrast materials, resulting in an undesired quenching of the T1 effect [96,99]. On the basis of this consideration, Cheon and colleagues proposed a “magnetically decoupled” core-shell design, which is composed of a superparamagnetic nanoparticle (core), SiO2 (separating layer), and paramagnetic material (shell), to develop a dual-mode artifact filtering nanoparticle imaging agent (AFIA) [101,102]. In their study, the T2 contrast material, MnFe2O4 (with diameter of 15 nm), and T1 contrast material, Gd2O(CO3)2 (with a thickness of 1.5 nm), were used as core and shell, respectively, and separated by a layer of SiO2 with thicknesses of 4, 8, 12, 16, and 20 nm [101]. It was found that the degree of T1 and T2 effect can be tuned

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by controlling the thickness of the separating layer, thus making it possible to create new T1/T2 CAs with maximized T1 and T2 effects. Later on, a variety of AFIAs were synthesized using a combination of different T1 and T2 nanomaterials in the core and shell while fixing the thickness of the separating SiO2 layer at 16 nm and the ability to perform the “AND logic gate” algorithm to enhance the accuracy of the raw MR images was demonstrated [102]. However, their large hydrodynamic sizes may result in short circulating times and poor colloidal stability under physiological conditions [103]. Alternatively, Gao and co-authors synthesized Gd2O3-embedded iron oxide (GdIO) nanoparticles based T1-T2 dual MR-CAs and demonstrated their applicability for the detection of hepatic tumors with great improvement in accuracy [96]. Ye and colleagues also synthesized PEGylated Gd3+ doped iron oxide nanoparticles with r1 and r2 values of 66.9 and 65.9 mM 1 s 1, respectively [104]. The in vivo MRI of these NPs demonstrated a brighter contrast enhancement in T1-weighted images and a simultaneous darkened effect in T2-weighted MR images compared to the precontrast images in the region of glioma [104]. Furthermore, Lee and colleagues integrated MnO and Fe3O4 NPs into a single Fe3O4/MnO hybrid nanocrystal, which showed T1-T2 MR imaging ability for the hepatocellular carcinoma tumor with a better visibility [105,106]. A “smart” lanthanide-based theranostic NaDyF4:Yb/NaGdF4:Yb,Er nanoprobe was reported by Zhang et al., with an excellent dark T2-weighted contrast and tunable bright T1weighted contrast properties [107]. Further PEGylated NaGdF4:Yb,Er NPs have also been reported as dual-modal molecular probes for tiny tumor imaging in vivo [108].

12.3 SURFACE COATING AND FUNCTIONALIZATION OF MAGNETIC NANOPARTICLES Magnetic nanomaterials should possess colloidal stability in physiological media (blood, plasma, lymph, urine) along with good biocompatibility and prolonged vascular retention to be considered for in vivo imaging. Without any surface modification, most of the magnetic nanomaterials have hydrophobic surfaces with a large surface area to volume ratio and due to hydrophobic interactions these particles tend to agglomerate and form larger clusters, resulting in increased particle sizes [24]. These agglomerations/clusters have strong dipoledipole interactions and ferromagnetic behavior, due to which these clusters get further magnetized in the presence of a magnetic field, causing a stronger attraction between the particles and, consequently, creating increased aggregation [109]. Another issue is that these NPs rapidly get coated by plasma proteins through opsonization immediately after being injected into the blood stream, which renders the particles recognizable by the body’s major defence system, the reticuloendothelial system (RES) [110,111]. The physicochemical factors

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that affect the opsonization process are the size, surface charge density, and hydrophilicity/hydrophobicity balance of NPs [40]. Usually, the smaller size MNPs with more neutral and the more hydrophilic carrier surface have the longer plasma half-life and thus the most promising strategy to reduce the RES uptake and to impart stability to NPs for their longer circulation times in blood involves: (1) sterically stabilizing the nanoparticles surface [112,113] and (2) reducing the particle size [114]. Therefore, for in vivo applications, the magnetic nanoparticles would require proper surface modifications to endow them with hydrophilic properties, to ensure the nontoxicity, biocompatibility, and stability to the RES, and to prevent nanoparticles agglomeration. In addition, these coatings also enable the functionalization of MNPs for conjugation with biomolecules, ligands for active targeting of the diseased tissue, encapsulation of drugs, etc., and thus help obtain more multifunctional MNPs. Stabilization of magnetic nanoparticles in aqueous solutions can be achieved using monomeric organic stabilizers, polymeric coatings, and/or inorganic coatings [24,115–117], and is discussed below briefly.

12.3.1 Monomeric Organic Stabilizers Nanoparticles prepared in organic solvents are frequently stabilized by surfactants bearing functional groups like carboxylate, phosphate, or sulfate as hydrophilic head groups, which bind to the surface of the nanoparticles and the hydrophobic hydrocarbon tails facing the solvent. Due to the affinity of the surface atoms of NPs for these functional groups, surface functionalization with proper hydrophilic ligands allows the phase transfer of nanoparticles from organic media to aqueous media [45]. The surfactants used for the stabilization of NPs studied so far include alkanesulfonic and alkanephosphonic acids [118,119], oleic acid [90,120,121], lactobionic acid [122], lauric acid [120,123], dodecylphosphonic and hexadecylphosphonic acids [120], or phosphonates [124], etc. For example, the surface coatings of magnetite NPs by oleic acid, lauric acid, dodecylphosphonic acid, hexadecylphosphonic acid, dihexadecylphosphonic acid, etc., was carried out by Sahoo et al., to stabilize these nanoparticles in organic solvents [120]. It was reported that alkyl phosphonates and phosphates could be used for obtaining stable dispersions of magnetic nanoparticles by forming a quasibilayer structure with the primary layer strongly bound to the surface of these nanoparticles. The surface of magnetite nanoparticles can also be stabilized in an aqueous dispersion by the adsorption of citric acid; one such system is VSOP C184, where iron oxide particles has been stabilized by monomeric coating of citric acid [82]. Other coating molecules, such as gluconic acid, dimercaptosuccinic acid, phosphorylcholine, sodium oleate, dodecylamine, and sodium carboxymethylcellulose can also be used for the stabilization and the dispersibility of NPs in aqueous medium [24,114,118].

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Cheon and colleagues synthesized water-dispersible iron oxide nanoparticles using 2,3-dimercaptosuccinic acid (DMSA), which has a bidentate carboxyl group and successfully used them for in vivo MRI [125]. For further improvement of the biocompatibility of nanoparticles, the backbones of these ligands may be designed to contain biocompatible polymers, such as poly(ethylene glycol) (PEG) [45]. Hyeon and colleagues synthesized PEG-derivatized phosphine oxide (PO-PEG) ligands with biocompatible PEG tail group and a surface coordinating phosphine oxide head group to stabilize several kinds of oxide nanoparticles in aqueous media [126].

12.3.2 Polymeric Stabilizers A variety of hydrophilic natural and synthetic polymers have been evaluated for use as coating materials for MNPs due to their ability to prevent particle aggregation, increase solubility, and improve the stability of the particles. Examples include gelatin, dextran, chitosan, pullulan, etc., as natural polymers and poly(ethylene-co-vinyl acetate), poly(vinylpyrrolidone) (PVP), poly(lacticco-glycolic acid) (PLGA), poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(glyceryl monooleate) (PGMO), etc., as synthetic polymers [24]. To facilitate further the efficient attachment of these polymers onto the surface of the MNPs, several functional molecules such as Dimercaptosuccinic acid (DMSA), biphosphonates, or alkoxysilanes may be employed [116]. It has been reported that coating MNPs with hydrophilic polymers such as dextran, PEG, or PVP, or with proteins (e.g., lactoferrin or ceruloplasmin) can remarkably increase their plasma half-life from a few minutes to several hours or even days in some cases, as a result of the stealth properties conferred by the polymer shell [116]. Among the various natural polysaccharide based polymers, dextran has been the most widely utilized and successful polymer, as MNPs coated with this polymer have shown improved biocompatibility and tend to stay in circulation for relatively longer periods of time [40,127]. FDA approved dextran/ carboxy-dextran coated MNPs have already been used to image the spleen, liver, and lymph nodes [32]. Alginate, an electrolytic polysaccharide with many carboxyl groups, has also been used for the coating and stabilization of magnetic nanoparticles [128–130]. In addition to these polysaccharides, chitosan is also gaining importance as a desirable coating material for MNPs, due to its biocompatibility and ample reactive functional groups, which can be utilized as anchors for conjugation of therapeutics, targeting ligands, and imaging agents [131–133]. PEG is another widely used polymer for nanoparticle coating, due to its antifouling nature that supports a resistance to protein adsorption and an ability to bypass the RES and natural barriers, such as the nasal mucosa, and thus leading to extended blood circulation times [134,135]. Because PEG itself is very inert, various strategies have been proposed for attaching PEG to MNPs, such as

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polymerization at the NP surface [136,137], modification through the sol-gel approach [138], or silane grafting onto the oxide surfaces [139,140]. Several studies have reported the use of PEG to increase the colloidal stability and biocompatibility of the iron oxide dispersions and blood circulation times [114]. Feruglose (Clariscan) is a commercial product that was developed using a PEGylated starch coating [141]. It has been demonstrated that the coating of iron oxide NPs by the protein-resistant copolymer poly(3-(trimethoxysilyl) propyl methacrylate-co-poly(ethylene glycol)methacrylate) [poly(TMSMAco-PEGMA)], which is composed of silane-anchoring moieties and PEG branches, assured an improved accumulation of the MNPs system into the mice tumor xenografts [142]. Coatings of gadolinium oxide nanocrystals using PEG-silane derivatives have also been reported, which resulted in an enhanced relaxivity while preventing the aggregation of the NPs [46,143]. PLGA has also been widely used to coat MNPs due to its biocompatible nature and ability to provide the sustained release of encapsulated drugs and/or contrast agents throughout the polymer degradation time to ensure prolong treatment [144]. For example, Chattopadhyay et al. prepared PLGA coated magnetite particles which showed sustained drug release for a period of 9 h and could also be used for MRI [145]. Coating iron oxide nanoparticles using a long chained PGMO polymer improved the aqueous stability of the particles without the use of surfactants [146]. Other polymers and copolymers that have been used to coat magnetic nanoparticles are PVP [147,148], poly(acrylic acid) (PAA) [149–151], polyethylenimine (PEI) [152,153], polyvinyl alcohol (PVA) [154,155], polysodium-4styrene sulfonate [156], poly(trimethylammonium ethylacrylate methyl sulfate)-poly(acrylamide) [157], polyvinylbenzyl-O-beta-D-galactopyranosyl-D-gluconamide (PVLA) [158], polymethacrylic acid [159], gummic acid [160], polycaprolactone [161], polyalkylcyanoacrylate [162], and poly(lactic acid) [163]. In addition, the coating of magnetic nanoparticles with proteins, such as human serum albumin (HSA) [164], avidin [165], and Annexin A5 (anxA5)-VSOP [166], has also been carried out to prepare stable and biocompatible magnetic fluids. Double- and single-stranded Deoxyribonucleic acid (DNA) have also been shown to be very good stabilizers for magnetic iron oxide nanoparticles, allowing the preparation of highly stable magnetic fluids with unprecedented high relaxivities [167]. These surface-modified magnetic nanoparticles with certain biocompatible polymers have intensively been studied as contrast agents for MRI and for magnetic-field-directed drug targeting. However, sometimes a thin polymer coating is not very suitable to protect very reactive MNPs. Also, metallic MNPs, stabilized by single or double layers of surfactants or polymers, are not air stable, and are easily leached by acidic solution, resulting in the loss of their magnetization [117,168]. Therefore, the development of other methods for stabilization of magnetic nanoparticles is of great importance.

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12.3.3 Inorganic Coatings Magnetic nanoparticles can be coated with inorganic materials like precious metals, carbon, silica (e.g., Ag and Au), or metal oxides [117]. These coatings not only provide stability to the nanoparticles in solution, but also help in binding various biological ligands to the nanoparticle surface. With these surface coatings, nanoparticles act as an inner core with an outer metallic shell of inorganic materials. Among precious metals, Gold is a widely used coating material owing to its low reactivity and its specific surface derivative properties for subsequent treatment with chemicals or biomedical agents. For example, it is well established that Au NPs surfaces could be functionalized with alcohol or carboxylic acid-terminated thiols, which further allow the linkage of functional ligands of interest for biomedical applications [169–171]. For instance, Carpenter [172] synthesized metallic iron particles coated by a thin layer of gold shell, which protects the iron core against oxidation and also provides functionality, making these composites applicable in biomedicine. Zhou et al. synthesized gold coated iron core-shell structure nanoparticles (Fe/Au), of an average size of about 8 nm with about 6 nm diameter core and 1–2 nm shell, which were stable under neutral and acidic aqueous conditions [173]. Carbon-coated magnetic nanoparticles have also received considerable attention in recent years due to very high chemical and thermal stabilities of carbon as well as improved biocompatibility [117]. Carbon-coated nanoparticles are generally present in the metallic state, and therefore have a higher magnetic moment than the corresponding oxides, along with high stability against oxidation and acid leaching [117,174,175]. Silica coated onto MNPs represents one of the most frequently used inorganic coatings as it improves the stability of magnetic nanoparticles, protects them from oxidation, and also reduces any potential toxic effects of the nanoparticles [25]. Another advantage of having a surface enriched in silica is the presence of surface silanol groups that can easily react with various coupling agents to covalently attach specific ligands to these magnetic particles [176]. For example, amine groups have been introduced on the surface of silica-coated magnetite nanoparticles by hydrolysis and condensation of an organosilane on the surface of magnetite nanoparticles [177,178]. The strong binding makes desorption of these ligands a difficult task. Furthermore, the silica surface can be easily functionalized, enabling the chemical bonding of various biological molecular species to the surface for site-specific targeted delivery [115]. Several authors have reported the surface coating of iron oxide NPs with silica to produce stable nano-dispersions in nonaqueous solvents [179–181]. Ferumoxsil, a well-known, orally administered clinical gastrointestinal tract imaging contrast agent is based on silica-coated magnetite particles functionalized with [3-(2 aminoethylamino)propyl]trimethoxysilane [73,74]. In another study, Sen et al. [182] reported the fabrication of magnetic mesoporous silicamagnetic nanocomposite with a surface area 10 times greater than the magnetite

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FIG. 12.4 Transmission electron microscopy images of (A) Fe3O4 particles, (B) silica coated Fe3O4 particles (Fe3O4@nSiO2), (C–E) perpendicularly aligned mesoporous silica shell (Fe3O4@nSiO2@mSiO2) microspheres, and (F) SEM image of Fe3O4@nSiO2@mSiO2 microspheres. (Reproduced with permission from Y. Deng, D. Qi, et al., J. Am. Chem. Soc. 130 (2008) 28–29. Copyright © 2008 American Chemical Society.)

core (25 vs. 250 m2 g 1) and showed its potential for application in magnetic bioseparations. Deng et al. also prepared core-shell magnetic mesoporous silica microspheres (Fe3O4@nSiO2@mSiO2) with a silica-coated magnetite core and perpendicularly aligned mesoporous silica shell using a surfactant-templating approach [183]. Fig. 12.4 demonstrates the transmission electron microscopy (TEM) images of the obtained microspheres at different steps. The obtained microspheres possess high magnetization, high surface area, large pore volume, and uniform accessible mesopores and have shown potential as a reusable absorbent for fast, convenient, and highly efficient removal of microcystins. The encapsulation of iron nanoparticles into iron oxide shell has also been reported, which provided a robust protective coating against deep oxidation and minimized the chemical instability and aggregation tendency of iron [184,185]. Vasile and colleagues synthesized discrete iron/iron carbide core and iron oxide shell NPs of  15 nm diameter with very few particle aggregates [186]. Metal oxides, such as titanium oxide [187], zirconium oxide [188], and aluminum oxide [189–192], have also been used as coatings for magnetic iron oxide nanoparticles and further, the surfaces of these metal oxides can be modified with phosphorylated molecules for biological applications [191]. Inorganic matrices such as zeolite or hydrotalcite have also been used to coat the magnetic NPs

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(e.g., Co, Fe, FeCo, Fe3O4, γ-Fe2O3, etc.) [193–197]. However, the safety and biocompatibility of these inorganic coatings still needs to be explored for biomedical applications. After the surface coating and stabilization of magnetic nanoparticles, functionalization and targeted vectorization is usually carried out to improve their performance for biomedical applications, as discussed in the next section.

12.3.4 Functionalization of Coated MNPs With Targeting Ligands The major challenge that underlies the use of nanoparticle therapy is the specificity of NPs for select organ/tissue or cells in the body. The NPs can be engineered to have an affinity for target tissues through passive, active, and magnetic targeting approaches. Passive targeting utilizes the physicochemical characteristics of NPs such as size, shape and surface properties to migrate and/or accumulate the NPs into the organ/tissue. In particular, the enhanced permeation and retention effect (EPR) can be used to target solid tumor tissue (Fig. 12.5A) [198,199]. Generally, in tumor tissue the production of new blood

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FIG. 12.5 Schematic illustration of different targeting strategies for systemic navigation of magnetic nanoparticles to the tumor site (A) passive targeting via the EPR effect, (B) active targeting via ligand grafting at the surface of nanocarriers, (C) magnetic targeting via placing magnet near the tumor site, and (D) the combination of magnetic and active targeting.

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vessels occurs rapidly with poor organization, which leads to many leaky fenestrations enabling the extravasation of NPs out of the vasculature, into the tumor tissue and thus the NPs tend to accumulate at tumor sites due to relatively inefficient lymphatic drainage [199]. For instance, iron oxide nanoparticles have successfully been used to image tumors without any targeting probes, that is, through passive targeting [142]. Though passive targeting facilitates the efficient localization of nanoparticles into the tumor site, it cannot promote their uptake by cancer cells. Also sometimes the enhanced permeability and retention is not suitable or inefficient and is available only for certain in vivo applications. In such cases, the accumulation and cellular uptake of NPs into the tumor site can be achieved by active targeting as shown in Fig. 12.5B, that is, by surface functionalization of NPs with homing moieties such as receptors or other surface membrane proteins overexpressed on target cells, which possess the inherent ability to direct selective binding to cell types or states [200]. For example, in the case of cancer, the surface conjugation involves specific ligands possessing high affinity towards the unique molecular signatures found on malignant cells or on endothelial cells lining the tumor neovasculature [201,202]. Currently, all approved and marketed nanoparticle therapies are passively targeted; however, intensive research is currently being undertaken to develop activelytargeted magnetic nanoparticles. In general, various categories of targeting ligands have been employed for tissue-specific targeting of magnetic nanoparticles for various biomedical applications: (1) Proteins such as transferrin, which is widely applied as a targeting ligand in the active targeting of anticancer agents that target the primary proliferating cells via transferrin receptors overexpressed on a variety of tumor cells [203]; lactoferrin, which acts as an antiinfective agent, as a modulator of the inflammatory response and iron absorption and as an immuno-regulatory protein with receptors on brush-border cells, polymorphonuclear leukocytes, etc. [24,138,204]. Ceruloplasmin, a copper transport protein which plays an important role in iron homeostasis and is also an effective antioxidant for a variety of free radicals [138,204]; elastin, a cross-linked protein in the extracellular matrix that provides elasticity for many tissues and is used for the thermal targeting of therapeutics to solid tumors [205]; albumin, a blood protein used to transport hydrophobic nutrients and energy to the tissues and bind to receptors on the surface of blood vessels [206]; and annexin V, which recognizes and binds to the phosphatidyl serine receptors expressed on the apoptotic cell surface [207]; (2) peptides such as RGD (arginine-glycine-aspartate sequence), which recognizes and binds to αvβ3 integrins that are overexpressed on a variety of angiogenic tumor endothelial cells and increases cell spreading and differentiation, as well as enhancing DNA synthesis [208]; transactivator of transcription (TAT)-peptide, which is a membrane-permeating peptide and enhances the intracellular delivery [209,210]; and (3) nucleic acid ligands, that is, aptamers that target specific antigen types expressed/overexpressed on the cancer cells (e.g., prostate specific membrane antigen) [211–215]. Monoclonal

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antibodies (mAbs) have also been used to deliver MNPs to tumor tissue due to their ability to target tumor associated cell surface antigens [216]. For example, Adcetris, an FDA approved conjugate of the anti-CD30 mAb brentuximab and vedotin, delivers enhanced clinical performance in the treatment of refractory Hodgkin’s Lymphoma [217]. Small molecule targeting ligands may also be employed as homing devices for tumor targeting, due to their better chemical stability than proteins and peptides, ease of conjugation with nanoparticles, and the potential low cost. Furthermore, they offer the possibility of increasing the affinity of MNPs towards the cancer cells through multivalent attachment [218,219]. Vitamin B9 (folic acid) is a small molecule high affinity targeting ligand used for the detection of cancer cells overexpressing the folate receptor in many types of human cancers [138]. It has been demonstrated that nanoparticles conjugated with folic acid can be actively internalized via receptor-mediated endocytosis and effectively directed to folate receptor-positive cancer cells [220,221]. Anisamide has also been demonstrated as a sigma receptor ligand, which can target nanoparticles to sigma receptor-positive tissues [222]. Carbohydrates such as lactose, glucose, and mannose that interact weakly with some cell surface receptors, can also serve as nanoparticle small molecule targeting ligands [223]. For example, natural ligands such as asialofetuin, or synthetic ligands with galactosylated or lactosylated residues, such as galactosylated cholesterol, glycolipids, or galactosylated polymers, that can bind to the asialoglycoprotein receptors (ASGP-R) overexpressed by the hepatocytes can be used for the specific targeting of hepatocytes [224]. Recently, a magnetic targeting study showed magnetic nanoparticles guided to the tumor site using magnetic fields, as shown in Fig. 12.5C. Furthermore, the combination of active and magnetic targeting (Fig. 12.5D) has also been hypothesized to enhance the multifunctional nanoparticles concentration in the tumor tissue for a better anticancer efficacy and increased contrast enhancement in MRI [225]. Among the various MNP assemblies, a number of SPION systems have implemented targeting ligands into their design with varying success, including small organic molecules [226–228], peptides [229–233], proteins [234], antibodies [235–237], and aptamers [213,214]. For example, Cheon and colleagues synthesized Herceptin-conjugated iron oxide nanoparticles and delivered the NPs selectively to the tumor tissue and internalized them into the tumor cells by interactions with the human epidermal-growth factor receptor (HER2/neu), as overexpressed in breast cancers [125]. Also, Zhang and colleagues conjugated PEG-coated iron oxide nanoparticles with targeting peptides (chlorotoxin) that were preferentially accumulated within gliomas and exhibited highly contrast enhanced MR images [238]. SPIOs NPs derivatized with annexin V have also been used for imaging in rabbit models of human atherosclerosis [38]. These targeted nanoparticles were found to produce high negative contrast images at 2000-fold lower doses than those reported for nonspecific atheroma uptake of untargeted superparamagnetic nanoparticles

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in the same animal model. Leonard and colleagues have reported the synthesis of amino-functionalized SPIONs (ASPIONs) and lactose-derivatized galactoseterminal-ASPIONs for the specific targeting of the asialoglycoprotein receptors overexpressed at the surface of the hepatocytes [239]. Recently, aptamer (AS1411)-conjugated Mn3O4@SiO2 core-shell nanoprobes were evaluated in human cervical carcinoma tumor-bearing mice and demonstrated an effective targeting of nucleolin-positive tumors [240]. Also recently reported was the surface functionalization of lanthanide based upconverting NaGdF4:Yb,Er NPs nanoparticles with cyclin D-specific peptides, which can target the CDK4/cyclin D complex and showed promising cytotoxicity towards cancer cells [241].

12.4 DISEASE THERAPY USING MAGNETIC NANOPARTICLE-BASED THERANOSTICS Theranostics is a system that integrates targeting, therapeutic, and diagnostic functions within a single platform [242]. Presently, the diagnostic, treatment, and therapeutic procedures are carried out separately for most of the diseases [243,244] that require a long time period, for example to evaluate drug efficacy, and then adjust the treatment plan accordingly, resulting in loss of opportunity for effective treatment, especially for rapidly progressing cancers [245]. On the other hand, theranostics deals with the development of more specific, individualized therapies for various diseases, and seeks to combine diagnostic and therapeutic capabilities into a single agent, thus leading to a promising therapeutic paradigm involving diagnosis, monitoring the early onset of diseases, and simultaneously carrying suitable therapeutic drugs to the diseased site in order to enhance therapeutic efficacy of treatment response [246,247]. The integrated theranostic approach is less time consuming and eventually allows for a quicker and more accurate decision, enabling better outcomes. It is assumed that theranostics will result in the acceleration of drug development, improved disease management, reduced risk, and reduced cost [247]. Magnetic nanoparticles are ideal candidates for the development of advanced theranostic systems that can co-deliver therapeutic and imaging functions due to their multifunctional properties [144]. Numerous studies have explored the potential of MNPs as theranostics agents for the management of diseases such as cancers and cardiovascular diseases. MNPs have been examined as platforms for a number of applications, such as drug delivery, hyperthermia, phototherapy, gene delivery, controlled drug release systems, etc. A few of them are described briefly in the following sections.

12.4.1 Targeted Drug Delivery The major disadvantages of most chemotherapy approaches are the lack of drug specificity towards a pathological site, general systemic distribution throughout

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the body (resulting in adverse side effects as the drug attacks normal, healthy cells in addition to the target tumor cells), the necessity of a large dose to achieve high local concentration, and nonspecific toxicity [248]. Utilizing potent drugs that are highly toxic to both cancerous and normal cells is a specific challenge in cancer chemotherapy. However, recent advances in nanomedicine have shown promise for targeted delivery of therapeutic agents with natural and engineered nanomaterials. Targeted delivery of drug molecules with MNPs has been shown to improve treatment efficacy by biodistribution and to protect the drugs from the microenvironment, exhibiting higher internalization by cancer cells than healthy cells, thereby enhancing the drug specificity and permitting the use of lower doses to reduce the toxicity of chemotherapy [249,250]. For example, three different ways to treat tumor using magnetic nanoparticles are: (1) by conjugating specific antibodies to the MNPs that can selectively bind to related receptors and inhibit tumor growth; (2) drug targeting, that is, drugs can be loaded onto the MNPs for targeted therapy and (3) targeted magnetic hyperthermia [251,252]. For drug targeting, the therapeutic agents/cytotoxic drugs are attached to or encapsulated within the biocompatible MNPs’ carrier to form the MNPs/drug co-complex. These drug/carrier complexes are then injected intravenously into the bloodstream and then concentrated in the desired location by external applied high-gradient magnetic fields. Once the drug/carrier is concentrated at the target, the drug can be released either via enzymatic activity or changes in physiological conditions, such as pH, osmolality, or temperature, and be taken up by the tumor cells [253]. The design and preparation of MNPs/drug co-complex requires MNPs as core materials and surface modified with various functional organic materials with the capacity to incorporate payload drugs and further to improve drug solubility for the systemic delivery. The most commonly used drug loading methods include direct encapsulation or adsorption of the drugs through physical interactions (e.g., hydrophobic interaction or electrostatic attraction) between the MNPs and the drug molecules or chemical reactions (e.g., covalent bonding through active groups) between the surface functional groups of MNPs and drug molecules [254]. To further enhance the target specificity, the drug/MNPs complex is associated with other homing moieties/ligands of specific recognition and binds to the target site. As discussed previously, the most common type of targeting ligands are antibodies, proteins, peptides, hormones, aptamers, and low molecular weight ligands, such as folate, etc. Antibodies and other functional proteins are natural choices of targeting ligands due to their high specificity and affinity towards the disease biomarkers. Also, some antibodies carry the therapeutic effect by themselves. For instance, a monoclonal antibody Herceptin (known as trastuzumab) is used as the ligand for targeting HER2-positive breast cancer and has also been used to treat early stage breast cancer with high expression of HER2/neu receptor [255]. It has been shown to improve the overall survival and disease-free

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survival of HER2-positive breast cancer patients [255,256]. Recently, Yang and colleagues used near-infrared dye NIR-830 labeled insulin-like growth factor 1 (IGF-1) as a targeting ligand to conjugate with iron oxide NPs for targeted delivery of Dox into IGF-1R positive pancreatic cancer in a orthotopic human pancreatic cancer patient tissue derived xenograft model (PDX) in nude mice and demonstrated the cell proliferation and induced apoptotic cell death of pancreatic cancer cells [257]. Among the low molecular weight ligands, Methotrexate (MTX) conjugated MNPs have been studied for targeted MR imaging and drug delivery of glioma [251,258]. Furthermore, integrins and RGD peptides have also been used as nanoparticle targeting ligands to facilitate tumor specific molecular imaging and drug delivery [254]. The aptamer-MNPs systems were also tested for targeted imaging/therapy in prostate cancer [211,259] and colorectal cancer [260]. To date, a variety of magnetic nanoparticle carriers have been developed and tested to deliver drugs to specific target sites in vivo on animal models and research continues in this direction. For instance, Widder et al. coupled the drug doxorubicin to the magnetic albumin particles and targeted it to sarcoma tumors implanted in rat tails [261]. The results demonstrated total remission of tumor in the magnetic-targeting group, while there was no evidence of remission in the control group that was administered with 10 times the dosage but without magnetic targeting. Tumor remission has been achieved in a variety of other animal studies, including rabbits, rats, and pigs [253,262–265]. Furthermore, MNPs have been evaluated for targeted drug delivery of a variety of traditional drugs including etoposide, doxorubicin, and methotrexate for potential treatment of diseases ranging from rheumatoid arthritis to highly malignant prostate and breast cancers [258,266–268]. Although considerable achievements have been reached in in vivo applications to date, actual clinical studies are still problematic and thus the application of magnetic drug targeting in humans has not reached the marketplace. The first clinical trials in humans with magnetic drug targeting was reported by Lubbe et al. [262,269,270] using a ferrofluid (particle size 100 nm) loaded with the drug epirubicin and directed towards solid tumors, demonstrating the successful accumulation of MNPs at the target site in approximately half of the patients. Another Phase I/II trial was conducted by Wilson et al. in 2004 on four patients with inoperable hepatocellular carcinoma, who were treated with a magnetic carrier bound to doxorubicin (MTC-DOX), which was targeted to the liver via transcatheter delivery through the hepatic artery under concurrent MR imaging [271]. The results demonstrated that the nanoparticles/drug complex was well focused at the tumor sites with 64%–91% of treated tumor volume, while the fraction of affected normal liver volume ranged from 7% to 30%, providing an indication that the combination of MR imaging and angiography could be used in some cases to optimize magnetic targeting. Furthermore, the potential of MNPs in antisense and gene therapy is also being assessed, which is discussed in later sections.

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12.4.2 Magnetic Hyperthermia The discriminatory killing of cancer cells without destroying healthy cells has long been a desired goal in cancer therapy. However, the various procedures used for cancer treatment, including chemotherapy, radiotherapy, or surgery, can fall short of this aim. A useful therapeutic modality for treating malignant tumors is hyperthermia, which selectively kills the tumor cells over healthy cells by heating a tumor at temperatures from 42 to 46°C. The currently available techniques for the induction of hyperthermia are ultrasound, radiofrequency, microwaves, infrared radiation, magnetically excitable thermoseeds, and tubes with hot water [9]. However, there are many challenges in these traditional hyperthermia treatments, for instance either healthy tissue being damaged by heating, or the limited penetration of heat into body tissues. Magnetic nanoparticle induced hyperthermia treatment has gained attention recently as an auxiliary treatment to chemotherapy, radiotherapy, and surgery in cancer therapy [24,111]. The idea of using MNP-based hyperthermia is based on the fact that when magnetic nanoparticles are exposed to an alternating current (AC) magnetic field, heat is generated by the magnetic hysteresis loss, Neelrelaxation, and Brown-relaxation [272,273]. It is well known that tumor cells are more sensitive to temperature increases than healthy cells, therefore when MNPs are injected into an organ with a tumor, they tend to accumulate in the tumor, due to the unorganized vasculature (as described earlier), and are remotely heated using an applied AC magnetic field to the required hyperthermic temperatures (42–45°C) [274,275]. Compared to traditional hyperthermia treatment, MNP-based hyperthermia offers several advantages such as the increased effectiveness, specificity, and safety of hyperthermia. For example, the MNPs used for hyperthermia are in the range of a few tens of nanometers in size, thus allowing easy access into tumors after intravenous injection with the aid of the applied magnetic field [276] and can be tailored with cancerspecific binding agents to be targeted towards specific tumor tissues [277–279], and then the heating of MNPs by the externally alternating magnetic field (AMF) allows the localized killing of the tumor cells with minimum damage to normal tissue [280]. The first experimental investigations of the application of magnetic materials for hyperthermia were carried out in 1957 by Gilchrist et al. [281] using 20–100 nm size particles of γ-Fe2O3 exposed to a 1.2 MHz magnetic field. Since then, numerous studies have been carried out using different types of magnetic materials, ranging from well-known and well investigated iron oxide-based nanomaterials to metallic NPs, different field strengths and frequencies, and different methods of encapsulation and delivery of the particles [249,280]. Generally, the preferred magnetic fluids for hyperthermia treatment are suspensions of superparamagnetic particles with high heating capacity (greater saturation magnetization, optimal anisotropy and larger size), as these produce more heat per unit mass than larger particles [282]. Hyperthermia has been tested either by

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using MNPs coated with stabilizers or by using MNPs encapsulated into delivery nanocarriers like liposomes [10,283]. For instance, hyperthermic agents based on iron oxide like magnetite NPs (Fe3O4) stabilized by a variety of ligands (such as dextran [284], cationic liposomes [285], polyvinyl alcohol, hydrogel [286], lauric acid [287,288],) and maghemite NPs (γ-Fe2O3) stabilized by ligands like dextran have been studied [284,286]. Additionally, silica encapsulated manganese perovskite nanoparticles have also been investigated for magnetically induced hyperthermia [289,290]. Yet another category is based on ferrites, such as cobalt ferrites (CoFe2O4), manganese ferrites (MnFe2O4), nickel ferrites (NiFe2O4), lithium ferrites, mixed ferrites of nickel-zinc-copper, and cobalt-nickel ferrites [291–294]. FeCo metallic NPs with extremely high heating performances of 1300–1600 W/g have also been reported [295]. The promise of MNP-based hyperthermia as a minimal invasive treatment of malignant brain tumors has been evaluated on a glioblastoma rat model and in human patients [296–298]. Dextran- or aminosilane-coated iron oxide NPs have been used for thermotherapy in a rodent glioblastoma multiforme (GBM) model [299] and in a human clinical trial in patients with recurrent GBM [297,298]. It was shown that intra-tumoral injection of aminosilanecoated IONPs (core size 12 nm) as well as subsequent exposure to an AC magnetic field (100 kHz) in several sessions before and after adjuvant fractionated radiation therapy led up to 4.5-fold prolongation of survival in so-treated rats compared to the untreated control animals, while the dextran-coated particles did not indicate any advantage. A high concentration of IONPs (>100 mg/mL) was required to achieve effective thermotherapy, with a median peak temperature within the tumor of 51.2°C. In addition, van Landeghem et al. published postmortem neuropathological findings on GBM patients, who had undergone thermotherapy using magnetic nanoparticles [299]. Results indicated that MNPs were observed as aggregates and restricted to the site of injection, highlighting the need for multiple trajectories of instillation. Clinical experiences with MNP-mediated thermotherapy on prostate carcinoma [300] and other tumor entities [301] have also been published.

12.4.3 Hyperthermia-Based Controlled Drug Delivery The delivery of hyperthermic magnetic nanomaterials to a specific target site with minimal side effects is an important challenge in targeted hyperthermia. In this context, the efficacy of magnetic hyperthermia can be increased further by the use of tumor-targeted MNPs for delivery to a specific target site along with the added potential of drug payload [302]. For instance, the use of dextran-coated MNPs conjugated to breast cancer targeting chimeric L6 monoclonal antibody has demonstrated the feasibility of targeting specific cancer cells [303,304]. Similarly, superparamagnetic IONPs conjugated with specific tumor cell targeting ligands, such as folates, lipids vesicles, MAbs, and HER2 receptors [305–309], have been synthesized, which specifically bind to the

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tumor cells upon injection, undergo tumor cell internalization, and thereby increase the intracellular concentrations of MNPs. Furthermore, MNP-based hyperthermia can also be utilized for controlled release of encapsulated drugs. The use of magnetic fields for controlled drug release from large polymeric matrices has been reported in literature [310,311]. For instance, Yogo and colleagues found that when the antitumor drug tamoxifen (TMX) was loaded as the inclusion complex with surface-coated β-cyclodextrin (CD) polymer onto FA-decorated SPIONs and subjected to the AMF, the drug release from the CD polymer was triggered in response to the heat stimulus [312]. Therefore, the combination of magnetic fluid hyperthermia and chemotherapy (i.e., by including the anticancer drug into the magnetic nanocarriers) may be expected to produce a still more efficient antitumor response. For example, Peter and colleagues reported the synergistic effect of the combined treatment of tumor cells with cis-diamminedichloroplatinum(II)-loaded IONPs and hyperthermia [313]. It was reported that when IONPs coated with a thermosensitive polymer poly (N-isopropylacrylamide) (PNIPAAm) were exposed to an AMF, the heat induced by IONPs led to temperature-triggered drug release at tumor site. The temperature increase in response to the AMF makes the PNIPAAm polymer collapse, triggering the release of the encapsulated drug [314]. Hayashi and colleagues studied the in vivo therapeutic efficacy of the combination of magnetic hyperthermia and chemotherapy using smart NP carriers (abbreviated as Fe3O4/DOX/PPy-PEG-FA NPs) composed of a polymer with a glass-transition temperature (Tg) of 44°C, which contained clustered Fe3O4 NPs and DOX for the treatment of multiple myeloma. It was found that the combination of the duo destroys cancer cells in the entire tumor and achieves a complete cure in one treatment, without the recurrence of malignancy or any significant toxicity (Fig. 12.6) [315].

12.4.4 Magnetic Nanoparticle Mediated Transfection for Gene Therapy Gene therapy holds the potential to treat genetic disorders and other critical human pathologies like cancer, auto-immune disorders, and neurodegenerative disorders [316–325]. Genetic disorders are treated by providing the missing genetic material, by correcting defective genes, or by increasing the expression of genes already present [319]. On the other hand, silencing the expression of specific target genes (involved in the disease) by the application of small interfering RNAs (siRNAs) represents another innovative and promising therapeutic strategy, with potential benefits like high target specificity and nontoxicity compared with chemotherapy [326,327]. Over the years, the field of gene therapy has flourished and several therapeutic DNA and siRNA candidates have been identified. Some of the most promising candidates are already undergoing preclinical and clinical trials for the treatment of cancer (e.g., gynecologic, liver, lung, prostate cancer, etc.), respiratory diseases (e.g., cystic fibrosis),

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FIG. 12.6 (A) Illustration of smart NPs that produce heat in response to an alternating current magnetic field (ACMF) and sequentially release DOX, (B) demonstration of cancer treatment with the combination of magnetic hyperthermia (MHT) and chemotherapy using the smart NPs, (C) photograph and thermal image of a mouse exposed to ACMF for 20 min after injection with Fe3O4/DOX/PPy-PEG-FA NPs and average change of the tumor temperature of the mice injected with Fe3O4/DOX/PPy-PEG-FA NPs, Fe3O4/PPy-PEG-FA NPs, and no NPs with respect to ACMF exposure time, (D) follow-up pictures of mouse exposed to ACMF for 20 min after injection with Fe3O4/DOX/PPy-PEG-FA NPs, and (E) photographs of nontreated mice, mice treated with chemotherapy, mice exposed to ACMF, mice injected with Fe3O4/DOX/PPy-PEG-FA NPs intratumorally, mice treated with MHT, and mice treated with the combination of MHT and chemotherapy 45 days after treatment. (From K. Hayashi, M. Nakamura, et al., Theranostics 4 (2014) 834–844.)

and blood-clotting disorders (such as haemophilia) [323,328,329]. The uptake of DNA/siRNA by cells without a carrier system is possible, but naked DNA/ siRNA is mostly degraded with nucleases and activates the immune responses.

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Therefore, several challenges have often been associated with gene therapy, such as to transport the gene to the doorstep of targeted cells and then to cross the cell membrane and locate the nucleus. Magnetic nanoparticles assisted transfection is a relatively new and time-saving method to introduce nucleic acids into a target cell with increased efficiency [326,330,331]. In the last two decades, MNP-based transfection systems have been researched extensively to overcome internalization and intracellular trafficking problems [332–334], such as (1) enzyme degradation of coating-material/gene in the extra/intra cellular space, (2) inappropriate subcellular localization, (3) endosomal trapping of DNA/siRNAs in cells, (4) release of therapeutic DNA from the carrier, and (5) entry of therapeutic gene into the nucleus [321]. This approach is becoming increasingly popular because it outperforms most other nonviral transfection methods, in terms of both transfection efficiency and cell viability, as MNPs are biodegradable and nontoxic at the recommended doses. Studies related to enhancing the transfection efficiency have shown that the oscillating magnetic field further promotes MNPs mediated transfection [333,335]. Briefly, the MNP assisted transfection procedure is illustrated in Fig. 12.7. As depicted, this method involves the use of magnetic forces acting on MNPs (coated with positively charged polymer and carrying therapeutic DNA/RNA) to promote uptake of therapeutic DNA and siRNA into the cell. The genetically

Electric device generating oscillating magnetic field

Polymer coating

Magnetic core

siRNA

Size~100–200 nm

(A)

Coated magnetic nanoparticles carrying DNA

Plasmid DNA

Polymer coated MNP carrying therapeutic gene

(B)

Cells to be transfected which are then implanted into the patient for therapy

Oscillating magnetic field +magnetic hyperthermia (for releasing the gene)

Diseased site

(C) FIG. 12.7 Schematic showing the conceptual representation of magnet-assisted transfection system where (A) magnetic nanoparticles coated with positively charged polymer are used to carry functional genes within the cells using oscillating magnetic fields (B). (C) Schematic showing in vivo magnetofection.

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altered cells or tissues transformed from such cells are then implanted into recipient animals to treat the pathology under investigation. For systemic in vivo applications, the MNP assisted transfection method can also be used to deliver therapeutic genes to malfunctioning human cells through generating an oscillating magnetic field around the patient (Fig. 12.7C). Known as magnetofection, this has become the method of choice for inserting genes into cells and currently >160 mammalian and other eukaryotic cells are known to be successfully transfected using magnetofection, including embryonic stem cells, mesenchymal stem cells, neural cell lines, and the majority of primary cell lines [336]. These successful transfections have raised the hope that corrective gene transfer therapy could be routine in future clinical settings to treat genetic disorders that otherwise cannot be cured by any clinical/surgical procedure [316,321]. The gene therapy has also shown promising outcomes in many preclinical studies through alleviating the symptoms of diseases like progression of cancer. However, gene therapy is still far from routine, owing to various technical, logistical, and, in some cases, conceptual hurdles that need to be overcome. For example, how many genes will be required to achieve the outcome (which depends upon the disease to be cured), their cellular destination (i.e., if the delivered correcting gene is reaching the right type of cells) and intracellular trafficking towards the nucleus (i.e., gene phagocytized by the cell is where the genes instruct the cell to create beneficial proteins or will silence a rogue gene). MNP-mediated gene therapy holds the potential to overcome these various problems, however, the safety of the procedures should be established by further preclinical studies on animal models before starting clinical trials on humans [316,321].

12.5 MULTIMODAL BIOIMAGING The bioimaging techniques currently available in clinical settings are MRI, positron emission tomography (PET), computed tomography (CT), single-photon emission computed tomography (SPECT), optical fluorescence imaging, and ultrasound (US) imaging, etc. [337]. Some of these techniques enable entireorganism anatomical imaging (e.g., MRI or CT) and others provide more specific molecular imaging (e.g., PET, SPECT, optical fluorescence, or MRI) at subcellular resolution. Molecular imaging (MI) monitors and measures biological processes in living subjects noninvasively, in real time, and with potential for sequential, longitudinal monitoring [338,339]. However, these imaging modalities in clinical settings have their own unique advantages along with intrinsic limitations, such as poor spatial resolution, low sensitivity, and poor signal penetration through tissues, and thus single-modality imaging does not possess all the capabilities of comprehensive imaging [2,340]. For example, MRI and CT are noninvasive techniques for in vivo imaging and threedimensional tomography, with high spatial resolution, but limited by low target sensitivity [97]. On the other hand, PET imaging has very high target sensitivity

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with poor spatial resolution, while fluorescence imaging has relatively good sensitivity but suffers from low tissue penetration depths. In a nutshell, each imaging modality has its own merits and demerits and thus, to compensate for the deficiencies of a specific modality, multimodal imaging approaches, offering a combination of imaging techniques with different strengths, have been examined to enhance imaging sensitivity and accuracy [2]. For instance, the combination of MRI with PET or optical modalities provides more precise imaging information with more enhanced resolution and sensitivity than using either modality alone. However, the problem cannot be solved by simply adding two different classes of imaging probes together and therefore, multimodal contrast agents or imaging probes have been developed to solve this problem. Magnetic nanoparticles are an emerging instrument in the toolkit of these MI methods, because of their intense and stable output, large payload delivery, multimodal signaling capacity, strong target binding via multiple ligands, high surface area to volume ratio, and tunable biodistribution profiles [338]. In the following sections, advances in the development of multimodal MNPs for MRIoptical, MRI-PET/SPECT and MRI-CT dual-modal imaging are discussed along with their in vitro and in vivo biomedical applications.

12.5.1 MRI-Optical Imaging As discussed previously, MRI has become a prominent diagnostic technique in clinical medicine as it provides highly resolved three-dimensional images of living bodies, but it suffers from low sensitivity. One way to complement the low sensitivity of MRI is the addition of optical fluorescence modalities. Multifunctional magnetic nanoparticles linked with fluorescent dyes lead to a single nanoprobe that provides superior fluorescence and MR imaging capabilities through the synergistic enhancement of its respective components. To date, several types of MRI-optical magnetic nanoprobes have been reported, where optically active components are chemically or physically combined with magnetic nanoparticles [341–345]. The development of such smart bimodal magnetic nanomaterials has received considerable interest, due to their diverse range of applications in bioimaging, photothermal and photodynamic therapies, magnetic separation, detection and isolation of multiple tumors, and drug delivery [324]. For instance, near-infrared fluorescent (NIRF) nanoprobes with the combined capability of MR and Optical imaging have been prepared by conjugation of the indocyanine dye Cy5.5 to arginyl peptides coated cross-linked iron oxide nanoparticles [344]. The dual-mode capability of these probes has been demonstrated in vivo, where on a subcutaneous injection of the probe, axillary and brachial lymph nodes were darkened on MR images and easily delineated by NIRF imaging. Similarly, thermally cross-linked SPION NPs conjugating with Cy5.5 dye have been tested as MRI/optical dual-contrast agents for in vivo cancer imaging in Lewis lung carcinoma-bearing mice [343]. The injection of these nanoprobes resulted in a tumor specific T2 signal drop of 68% in MRI, with

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fluorescence lasting up to 4 h in optical imaging. Another nanoprobe (NPCP-CTX-Cy5.5) comprised of iron oxide nanoparticles coated with a PEGylated-chitosan branched copolymer and conjugated with a targeting ligand, chlorotoxin (CTX) and a near-infrared fluorophore, Cy.5.5, has been reported with the capability to selectively accumulate in brain tumors across the blood brain barrier [346]. However, combining fluorescent units with magnetic nanoparticles often suffers from fluorescence quenching due to the interaction of MNPs with the attached fluorochrome [344]. To overcome this issue, different strategies, like the utilization of long chemical linkers or a thick silica surface coating layer, have been implemented [347]. For example, “core-satellite” structured dual functional nanoparticles comprised of a Rhodamine-dye-doped silica (DySiO2) “core” and multiple “satellites” of iron oxide magnetic nanoparticles have been reported to detect neuroblastoma cancer cells via MRI along with subcellular fluorescence imaging [345]. Another class of multifunctional nanoprobes based on upconversion NPs (UCNPs) with combined optical and magnetic properties has been reported for multimodality imaging [341]. Liu and colleagues synthesized a UCNP-IONP complex by adsorbing ultrasmall superparamagnetic iron oxide nanoparticles onto the surface of a NaYF4-based UCNPs and demonstrated their applications for in vitro targeted upconversion luminescence (UCL), MR, and dark-field imaging; for molecular and magnetic targeted photo thermal therapies of cancer cells; and as a contrast agent for in vivo dual-modal UCL/MR imaging of lymph nodes in mice [341].

12.5.2 MRI-PET/SPECT Imaging Another important multimodal imaging system is achieved via the combination of MRI with radioisotope-based imaging techniques (e.g., PET or SPECT). Magnetic nanoparticles can be coupled with radionuclide labels (e.g., 18F, 64 Cu, 68Ga, and 124I for PET and 99mTc, 111In, and 131I for SPECT) for dualmode MRI-PET/SPECT imaging using a gamma camera and PET [97]. Usually, PET/SPECT imaging techniques use the intense γ-ray emission from radionuclide and offer higher sensitivity than MRI, but with the limitation of relatively poor spatial resolution [2]. Therefore, integrated MRI and PET/ SPECT dual-modal imaging agents have the potential to provide highly sensitive and high-resolution imaging in vivo. The majority of the MRI-PET/SPECT agents reported to date are based on the combination of PET/SPECT isotopes with superparamagnetic iron oxide nanoparticles [348–353]. For instance, Cheon and colleagues prepared Mn-doped ferrite nanoparticles (MnFe2O4) coated with serum albumin (SA) and linked 124I radionuclide via tyrosine residues of SA [353]. The resultant 124I-SA-MnMEIO MRI-PET dual imaging agent provided highly sensitive signals in both MRI and PET images. Another MRI-PET dual-mode imaging agent, based on iron oxide NPs coated with polyaspartic acid (PASP-IO) and coupled with DOTA chelators for 64Cu labeling

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(as PET detection motif ) and arginine-glycine-aspartic acid (RGD) peptide for selective targeting of tumor integrin αυβ3, has been developed for simultaneous PET and MRI of tumor integrin expression [350]. MRI/PET imaging showed integrin specific delivery with significant uptake of conjugated RGD-PASPIO nanoparticles in the reticuloendothelial system. In another work by Torres Martin de Rosales et al., 64Cu radiolabeling was performed directly on the inorganic surface rather than the SPION coating using a bifunctional molecule composed of dithiocarbamate (DTC) and bisphosphonate (BP) [349]. The final complex formed [64Cu (dtcbp)2] was then labeled with clinically available dextran-coated SPION (Endorem), due to the high affinity of BPs towards iron oxide. The MR-PET dual-modality imaging capabilities of [64Cu(dtcbp)2]Endorem were demonstrated in vivo by showing its accumulation in draining lymph nodes. Studies on MRI/SPECT dual-modality imaging have also been carried out by combining SPION with SPECT probes. For instance, Misri et al. developed dual-modality imaging bio-probes by conjugating 111In labeled antimesothelin antibody mAbMB to SPIONs, specifically for SPECT and MRI of mesothelinexpressing cancers [354]. The experimental findings demonstrated the ability of In-mAbMB-SPION agents to specifically localize in mesothelin-expressing tumors, which resulted in an enhanced MR contrast at tumor site. The biodistribution study using SPECT imaging also showed relatively low uptake in the other normal organs compared to the tumor, which correlated with autoradiography images. In another example, Strand and colleagues developed 99mTclabeled PEG-coated iron oxide as a MRI-SPECT dual-modal contrast agent for imaging a sentinel lymph node [355]. Recently, Sandiford et al. developed an MRI-SPECT dual-mode agent with high radiolabel stability using 99mTc labeled BP (PEG polymer conjugate containing a terminal 1,1-bisphosphonate), which binds irreversibly to the surface of ultrasmall superparamagnetic iron oxide nanoparticles [351]. The in vivo studies demonstrated the high potential of PEG(5)-BP-USPIOs as a contrast agent for MRI angiography with high spatial resolution. In addition, its optimal relaxivity properties allowed the use of a lower dose (4-fold) of contrast agent, compared to other USPIOs, to obtain a similar signal enhancement. Furthermore, the SPECT studies also confirmed low RES uptake and long blood circulation times for the agent. These results demonstrated the potential of PEG(5)-BP-USPIOs for the development of targeted multimodal imaging of vascular targets involved in cardiovascular and oncologic diseases.

12.5.3 MRI-CT Imaging Computed tomography (CT) is one of the most widely used imaging modalities to diagnose various diseases in the clinical field. However, despite several advances in the field of CT contrast agents, it suffers from short imaging times,

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due to rapid renal clearance, renal toxicity, and vascular permeation [356]. On the other hand, MRI has advantages over CT including high spatial resolution and sensitivity. Therefore, MRI and CT dual-modal imaging can be used to compensate for the weakness of each modality. Gold nanoparticles are most commonly used as CT contrast agents [357]. Tillement and colleagues encapsulated the Gold NPs cores within a multilayered organic shell composed of gadolinium chelates and applied them as contrast agents for both in vivo CT and MRI [358]. The contrast enhancement in MRI stems from the presence of gadolinium ions that are entrapped in the organic shell, whereas the gold core provides a strong X-ray absorption revealing the use of functionalized gold nanoparticles for dual-modality imaging. In addition, the combination of Gold and SPIOs NPs can be used for the development of MRI-CT dual-modal agents. For instance, Kim et al. developed a poly(ethylene glycol) (PEG) coated hybrid nanoparticle, comprised of an iron oxide nanoparticle core and a thin gold layered shell (GION), as a potential MRI-CT dual-contrast agent, which resulted in high CT intensity and mild MRI signal, presumably resulting from the embedding of SPIONs in the inner core due to the presence of gold [359]. To overcome this limitation, the same group designed a hybrid nanoparticle, in which several SPIONs were fused with a gold nanoparticle in a dumbbell-shaped manner [360]. The synthesized Au-Fe3O4 fused hybrid nanoparticles coated with poly(DMAr-mPEGMA-r-MA) had an improved in vivo CT contrast efficiency (1.6-fold) after 1 h postinjection in a murine hepatoma model. Also, the T2 relaxivity coefficient for the dual-mode agent was greater than that of Resovist. Magnetic nanomaterial based probes for trimodal imaging have also been evaluated in several studies. For example, Xie et al. developed a trimodal probe for MRI/PET/optical imaging based on IONPs [361]. In this report, IONPs were modified with dopamine in order to further coat the NPs with human serum albumin and were then conjugated with Cy5.5 dye and 64Cu-DOTA chelates. Using NIRF, PET, and MRI devices, tumor regions were clearly visualized after the trimodal probe was systemically administered into tumor-bearing mice. Recently, Zhou et al. developed Gd-DTPA and phosphorescent probe (iridium-complex)-modified NaDyF4 nanophosphors (DyNPs-Gd-Ir) as contrast agents for MRI/CT/Optical trimodal imaging [362]. The Dy in the host induces a high X-ray absorption ability for CT imaging and negative enhancement for T2-weighted MR imaging, whereas the positive contrast for T1-weighted MRI results from the Gd-DTPA. The SPIO nanoparticles conjugated with 64Cu and fluorescent dye as a trimodal probe was demonstrated for macrophage detection in atherosclerotic plaques [363]. Furthermore, magnetic nanoparticles have also demonstrated their utility in nontraditional multimodal imaging techniques, such as magnetic particle imaging (MPI), magnetomotive ultrasound imaging (MMUS), and magneto-photoacoustic imaging (MPA), that employ magnetic nanoparticles as a source of the imaging signals, which are beyond the scope of this chapter [364].

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12.6 CONCLUSIONS AND FUTURE PROSPECTIVE In this chapter, we presented recent advances in the development of magnetic nanomaterial based therapies for various biomedical applications. Particularly, progress in the diagnostic and therapeutic applications of MNPs, for example, as MRI contrast agents, in targeted drug delivery, magnetic hyperthermia, and magnetofection, has been discussed. Various formulations of MNPs are in their final development stages, with several already on the market, for their use in a variety of clinical applications (e.g., liver, spleen, lymph nodes imaging). Evolution of multifunctional magnetic nanoparticles as nano-platforms for fast and precise disease verification, localization of the diseased tissues, and quick delivery of drugs to the target site has shown great potential in the emerging field of personalized medicine. Such nano-systems enable the detection and monitoring of an individual patient’s cancer at an early stage, and deliver the anticancer drugs over a prolonged period for enhanced therapeutic efficacy. Further advances in MNPs technology, such as enhanced magnetic properties, nonbiofouling surface coatings, and the integration of targeting and therapeutic agents, continue to be evaluated in an effort to bring these nano-systems into clinical settings. For instance, targeted drug delivery of magnetic nanoparticles is currently undergoing preliminary human trials after successful tests in animals. Magnetic hyperthermia has also been proven to be efficacious for tumor treatment in animals, but is not yet accessible in humans. MNPs serving as multimodal imaging agents have also been actively pursued. The combinations of various types of materials (e.g., fluorescent molecules and radio nuclides) can provide magnetic nanoparticles with multimodal imaging capabilities and their use in multimodal bioimaging approaches has been intensively studied for a better understanding of critical molecular and cellular level information in biological systems and more accurate imaging of biological targets. While research in biomedical nanotechnology has substantially improved the design and safety of many nanomaterials, there is still a long way to go to address many challenges to establish the application of MNPs in clinical settings. For most of the in vivo applications, the safety and biocompatibility of MNPs are of crucial importance. The toxicity of magnetic nanoparticles is another critical issue that depends on numerous factors including the dose, chemical composition, method of administration, size, biodegradability, solubility, pharmacokinetics, biodistribution, surface chemistry, shape, structure, etc. [365], and thus the accurate assessment of nanoparticle toxicity require further investigations. Another important challenge is to direct the magnetic nanoparticle drug carriers to the desired target site for treatment as the magnetic gradient is currently generated using a permanent magnet placed near the target site [33,269,270], which is not ideal for particle focusing. Furthermore, the magnetic gradient from permanent magnets decreases with distance to the target and can only penetrate into a tissue depth of 8–12 cm [265,366], and thus cannot be applied for deeper tumors. Magnetic hyperthermia is also a promising

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application, but is limited by the fact that the tumor needs to be localized and therefore cannot be used for treating early-stage tumors. Thus, this technique requires further advances. In this chapter, we have focused only on a few of the many biomedical applications of magnetic nanoparticles that are currently being explored. Research is also being conducted on other biomedical applications such as magnetic twisting cytometry, magnetic separation, tissue engineering, magnetic biosensors, etc. For example, magnetic twisting cytometry is an active microrheology technique used to measure the mechanical properties of individual living cells and tissues. In this method, ferromagnetic microbeads bound to specific receptors on a cell wall get twisted by a measurable amount upon changing the direction of an applied magnetic field, which is related to the mechanical properties of cell membrane and cytoskeleton [367–370]. Another important application currently being pursued is tissue engineering, which offers new possibilities for the functional and structural restoration of damaged or lost tissue. In magnetic force-based tissue engineering, magnetic nanoparticles are attached to either the cell membrane, or to mechanosensitive ion channels in the membrane, and a magnetic force is applied, which activates the channels and initiates biochemical reactions within the cell to enhance bone cell adhesion and proliferation, thereby promoting the growth of functional bone and cartilage [116,249,371,372]. Magnetic separation is also a widely employed technique that has been used for the selection of rare tumor cells from blood and is especially well suited to the separation of low numbers of target cells and further allows detection of magnetically separated cells using MRI [373]. Furthermore, biosensing strategies based on MNPs have recently received considerable attention. Magnetic biosensors employ bio-receptor (such as an antibody or a strand of nucleic acid that selectively binds to the target analyte) coated MNPs for detecting biological interactions by monitoring the changes in magnetization, proton relaxation times, or magnetically induced effects, such as changes in coil inductance, resistance, or magneto-optical properties [374–376].

ACKNOWLEDGMENTS Anupam Guleria acknowledges the Department of Science and Technology (DST), Govt. of India for financial assistance under DST INSPIRE Faculty Award (Ref. no. DST/Inspire Faculty Award 2014/LSBM-120).

REFERENCES [1] [2] [3] [4] [5] [6]

L.E. Jennings, N.J. Long, Chem. Commun. (2009) 3511–3524. D.E. Lee, H. Koo, et al., Chem. Soc. Rev. 41 (2012) 2656–2672. S.M. Janib, A.S. Moses, et al., Adv. Drug Deliv. Rev. 62 (2010) 1052–1063. M.F. Bellin, Eur. J. Radiol. 60 (2006) 314–323. C. Burtea, S. Laurent, et al., Handb. Exp. Pharmacol. (2008) 135–165. G.J. Strijkers, W.J. Mulder, et al., Anti Cancer Agents Med. Chem. 7 (2007) 291–305.

382 Applications of Nanomaterials [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53]

C. Corot, P. Robert, et al., Adv. Drug Deliv. Rev. 58 (2006) 1471–1504. M. Babincova, P. Babinec, Biomed. Papers 153 (2009) 243–250. M. Johannsen, U. Gneveckow, et al., Int. J. Hyperth. 21 (2005) 637–647. A. Jordan, R. Scholz, et al., J. Magn. Magn. Mater. 201 (1999) 413–419. P. Cherukuri, E.S. Glazer, et al., Adv. Drug Deliv. Rev. 62 (2010) 339–345. L. Frullano, T.J. Meade, JBIC J. Biol. Inorg. Chem. 12 (2007) 939–949. J. Dobson, Drug Dev. Res. 67 (2006) 55–60. C. Sun, J.S.H. Lee, et al., Adv. Drug Deliv. Rev. 60 (2008) 1252–1265. O. Veiseh, J.W. Gunn, et al., Adv. Drug Deliv. Rev. 62 (2010) 284–304. C. Xu, L. Mu, et al., Nanotechnology 494001 (2011) 22. S.H. Hu, T.Y. Hsieh, et al., Adv. Healthc. Mater. 3 (2014) 273–282. A.P. Majewski, U. Stahlschmidt, et al., Biomacromolecules 14 (2013) 3081–3090. N. Pamme, C. Wilhelm, Lab Chip 6 (2006) 974–980. C. Wilhelm, F. Gazeau, Biomaterials 29 (2008) 3161–3174. N. Tran, T.J. Webster, WIREs Nanomed. Nanobiotechnol. 1 (2009) 336–351. R.A. Pareta, E. Taylor, et al., Nanotechnology 265101 (2008) 19. N. Bock, A. Riminucci, et al., Acta Biomater. 6 (2010) 786–796. A.K. Gupta, M. Gupta, Biomaterials 26 (2005) 3995–4021. P. Tartaj, M.D. Morales, et al., J. Phys. D. Appl. Phys. 36 (2003) R182. S. Laurent, S. Boutry, et al., Curr. Med. Chem. 16 (2009) 4712–4727. B. Bonnemain, J. Drug Target. 6 (1998) 167–174. J.L. Bridot, A.C. Faure, et al., J. Am. Chem. Soc. 129 (2007) 5076–5084. M. Engstrom, A. Klasson, et al., MAGMA 19 (2006) 180–186. R. Naccache, P. Chevallier, et al., Adv. Healthc. Mater. 2 (2013) 1478–1488. H.B. Na, J.H. Lee, et al., Angew. Chem. Int. Ed. Eng. 46 (2007) 5397–5401. J. Xie, S. Lee, et al., Adv. Drug Deliv. Rev. 62 (2010) 1064–1079. N. Tran, T.J. Webster, J. Mater. Chem. 20 (2010) 8760–8767. J. Xie, S. Jon, Theranostics 2 (2012) 122–124. C. Alexiou, R. Jurgons, et al., J. Nanosci. Nanotechnol. 6 (2006) 2762–2768. C. Tassa, S.Y. Shaw, et al., Acc. Chem. Res. 44 (2011) 842–852. D.D. Stark, R. Weissleder, et al., Radiology 168 (1988) 297–301. B.R. Smith, J. Heverhagen, et al., Biomed. Microdevices 9 (2007) 719–727. Z.R. Stephen, F.M. Kievit, et al., Mater. Today 14 (2011) 330–338. S. Mornet, S. Vasseur, et al., J. Mater. Chem. 14 (2004) 2161–2175. S.P. Lin, J.J. Brown, J. Magn. Reson. Imaging 25 (2007) 884–899. P. Caravan, J.J. Ellison, et al., Chem. Rev. 99 (1999) 2293–2352. L. Curvo-Semedo, F. Caseiro-Alves, MR contrast agents, in: Clinical MRI of the Abdomen: Why, How, When, Springer Berlin Heidelberg, Berlin, Heidelberg, 2011, pp. 17–39. P.H. Kuo, E. Kanal, et al., Radiology 242 (2007) 647–649. H.B. Na, I.C. Song, et al., Adv. Mater. 21 (2009) 2133–2148. M. Ahren, L. Selegard, et al., Langmuir 26 (2010) 5753–5762. J.Y. Park, M.J. Baek, et al., ACS Nano 3 (2009) 3663–3669. I.F. Li, C.H. Su, et al., Adv. Funct. Mater. 18 (2008) 766–776. F. Evanics, P.R. Diamente, et al., Chem. Mater. 18 (2006) 2499–2505. N.J.J. Johnson, W. Oakden, et al., Chem. Mater. 23 (2011) 3714–3722. Q. Ju, D. Tu, et al., J. Am. Chem. Soc. 134 (2012) 1323–1330. M.A. McDonald, K.L. Watkin, Investig. Radiol. 38 (2003) 305. M.A. McDonald, K.L. Watkin, Acad. Radiol. 13 (2006) 421–427.

Biomedical Applications of Magnetic Nanomaterials Chapter

12

383

[54] G. Liang, L. Cao, et al., J. Mater. Chem. B 1 (2013) 629–638. [55] H. Hifumi, S. Yamaoka, et al., J. Am. Chem. Soc. 128 (2006) 15090–15091. [56] Y.K. Gun’ko, D.F. Brougham, Magnetic Nanomaterials as MRI Contrast Agents, in: Nanotechnologies for the Life Sciences, Wiley-VCH Verlag GmbH & Co. KGaA, New Jersey, 2011. [57] N. Chen, C. Shao, et al., ACS Appl. Mater. Interfaces 6 (2014) 19850–19857. [58] M.J. Baek, J.Y. Park, et al., ACS Appl. Mater. Interfaces 2 (2010) 2949–2955. [59] J. Xiao, X.M. Tian, et al., Sci. Rep. 3 (2013) 3424. [60] N. Abrikossova, C. Skoglund, et al., Nanotechnology 275101 (2012) 23. [61] J.G. Penfield, R.F. Reilly, Nat. Clin. Pract. Nephrol. 3 (2007) 654–668. [62] C. Au, A. Benedetto, et al., Neurotoxicology 29 (2008) 569–576. [63] B.H. Kim, N. Lee, et al., J. Am. Chem. Soc. 133 (2011) 12624–12631. [64] U.I. Tromsdorf, O.T. Bruns, et al., Nano Lett. 9 (2009) 4434–4440. [65] C. Chambon, O. Clement, et al., Magn. Reson. Imaging 11 (1993) 509–519. [66] E. Taboada, E. Rodriguez, et al., Langmuir 23 (2007) 4583–4588. [67] S. Wagner, J. Schnorr, et al., Investig. Radiol. 37 (2002) 167–177. [68] M.H. Mendonca Dias, P.C. Lauterbur, Magn. Reson. Med. 3 (1986) 328–330. [69] R.C. Semelka, T.K. Helmberger, Radiology 218 (2001) 27–38. [70] P. Reimer, B. Tombach, Eur. Radiol. 8 (1998) 1198–1204. [71] W. Leenders, IDrugs 6 (2003) 987–993. [72] Y. Anzai, K. Blackwell, et al., Radiology 192 (1994) 709–715. [73] C.W. Jung, P. Jacobs, Magn. Reson. Imaging, 13 (1995) 661–674. [74] P.F. Hahn, D.D. Stark, et al., Radiology, 175 (1990) 695–700. [75] T.F. Jacobsen, M. Laniado, et al., Acad Radiol, 3 (1996) 571–580. [76] P. Reimer, C. Marx, et al., J. Magn. Reson. Imaging, 7 (1997) 945–949. [77] L. Grazioli, M.P. Bondioni, et al., J. Magn. Reson. Imaging, 29 (2009) 607–616. [78] S.J. McLachlan, M.R. Morris, et al., J. Magn. Reson. Imaging, 4 (1994) 301–307. [79] Y.X. Wang, Quant. Imaging Med. Surg, 1 (2011) 35–40. [80] W. Li, S. Tutton, et al., J. Magn. Reson. Imaging, 21 (2005) 46–52. [81] G.H. Simon, J. von Vopelius-Feldt, et al., Invest Radiol, 41 (2006) 45–51. [82] M. Taupitz, S. Wagner, et al., Investig. Radiol, 39 (2004) 394–405. [83] H.E. Daldrup-Link, A. Kaiser, et al., Acad. Radiol, 10 (2003) 1237–1246. [84] K.E. Kellar, D.K. Fujii, et al., J. Magn. Reson. Imaging, 11 (2000) 488–494. [85] J.M. Hill, A.J. Dick, et al., Circulation 108 (2003) 1009. [86] S. Maenosono, T. Suzuki, et al., J. Magn. Magn. Mater. 320 (2008) L79–L83. [87] G. Reiss, A. Hutten, Nat. Mater. 4 (2005) 725–726. [88] U.I. Tromsdorf, N.C. Bigall, et al., Nano Lett. 7 (2007) 2422–2427. [89] J.H. Lee, Y.M. Huh, et al., Nat. Med. 13 (2007) 95–99. [90] S. Sun, H. Zeng, et al., J. Am. Chem. Soc. 126 (2004) 273–279. [91] E. Terreno, D.D. Castelli, et al., Chem. Rev. 110 (2010) 3019–3042. [92] S. Viswanathan, Z. Kovacs, et al., Chem. Rev. 110 (2010) 2960–3018. [93] K. Kattel, J.Y. Park, et al., Biomaterials 33 (2012) 3254–3261. [94] G.K. Das, J. NJJ, et al., J. Phys. Chem. Lett. 3 (2012) 524–529. [95] K. Kattel, J.Y. Park, et al., ACS Appl. Mater. Interfaces 3 (2011) 3325–3334. [96] Z. Zhou, D. Huang, et al., Adv. Mater. 24 (2012) 6223–6228. [97] J. Cheon, J.H. Lee, Acc. Chem. Res. 41 (2008) 1630–1640. [98] E. Sook Choi, J. Young Park, et al., Eur. J. Inorg. Chem. 2010 (2010) 4555–4560. [99] A. Szpak, S. Fiejdasz, et al., J. Nanopart. Res. 16 (2014) 2678.

384 Applications of Nanomaterials [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131]

[132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145]

H. Yang, Y. Zhuang, et al., Biomaterials 32 (2011) 4584–4593. C. Js, J.H. Lee, et al., J. Am. Chem. Soc. 132 (2010) 11015–11017. T.H. Shin, J.S. Choi, et al., ACS Nano 8 (2014) 3393–3401. F. Hu, Y.S. Zhao, Nano 4 (2012) 6235–6243. N. Xiao, W. Gu, et al., J. Colloid Interface Sci. 417 (2014) 159–165. G.H. Im, S. Kim, et al., Biomaterials 34 (2013) 2069–2076. S. Li, C. Shao, et al., RSC Adv. 5 (2015) 33639–33645. Y. Zhang, G.K. Das, et al., Nano 6 (2014) 12609–12617. C. Liu, Z. Gao, et al., ACS Nano 7 (2013) 7227–7240. I.W. Hamley, Angew. Chem. Int. Ed. 42 (2003) 1692–1712. S.S. Davis, Trends Biotechnol. 15 (1997) 217–224. C.C. Berry, A.S.G. Curtis, J. Phys. D. Appl. Phys. 36 (2003) R198. E. Allemann, R. Gurny, et al., Eur. J. Pharm. Biopharm. 39 (1993) 173–191. U. Gaur, S.K. Sahoo, et al., Int. J. Pharm. 202 (2000) 1–10. S.M. Moghimi, A.C. Hunter, et al., Pharmacol. Rev. 53 (2001) 283–318. S. Laurent, D. Forge, et al., Chem. Rev. 108 (2008) 2064–2110. L.H. Reddy, J.L. Arias, et al., Chem. Rev. 112 (2012) 5818–5878. A.H. Lu, E.L. Salabas, et al., Angew. Chem. Int. Ed. 46 (2007) 1222–1244. D. Portet, B. Denizot, et al., J. Colloid Interface Sci. 238 (2001) 37–42. D.I. Kreller, G. Gibson, et al., Colloids Surf. A Physicochem. Eng. Asp. 212 (2003) 249–264. Y. Sahoo, H. Pizem, et al., Langmuir 17 (2001) 7907–7911. K. Woo, J. Hong, et al., J. Magn. Magn. Mater. 293 (2005) 177–181. K.M. Kamruzzaman Selim, Y.S. Ha, et al., Biomaterials 28 (2007) 710–716. M. Hodenius, M. De Cuyper, et al., Chem. Phys. Lipids 120 (2002) 75–85. D. Roberts, W.L. Zhu, et al., J. Appl. Phys. 87 (2000) 6208–6210. J. Yw, Y.M. Huh, et al., J. Am. Chem. Soc. 127 (2005) 5732–5733. H.B. Na, I.S. Lee, et al., Chem. Commun. (2007) 5167–5169. R. Weissleder, A. Bogdanov, et al., Adv. Drug Deliv. Rev. 16 (1995) 321–334. Y. Nishio, A. Yamada, et al., Polymer 45 (2004) 7129–7136. M.A. Morales, P.V. Finotelli, et al., Mater. Sci. Eng. C 28 (2008) 253–257. E. Kroll, F.M. Winnik, et al., Chem. Mater. 8 (1996) 1594–1596. H. Arami, Z. Stephen, et al., Chitosan-Coated Iron Oxide Nanoparticles for Molecular Imaging and Drug Delivery, in: Chitosan for Biomaterials I, Springer, Berlin, Heidelberg, 2011, pp. 163–184. H.S. Lee, E. Hee Kim, et al., J. Magn. Magn. Mater. 293 (2005) 102–105. L. HyoSook, S. Huiping, et al., IEEE Trans. Magn. 41 (2005) 4102–4104. R. Gref, Y. Minamitake, et al., Science 263 (1994) 1600. M. Tobio, R. Gref, et al., Pharm. Res. 15 (1998) 270–275. C. Flesch, Y. Unterfinger, et al., Macromol. Rapid Commun. 26 (2005) 1494–1498. J.F. Lutz, S. Stiller, et al., Biomacromolecules 7 (2006) 3132–3138. A.K. Gupta, R.R. Naregalkar, et al., Nanomedicine 2 (2007) 23–39. E.K.U. Larsen, T. Nielsen, et al., ACS Nano 3 (2009) 1947–1951. M. Pilloni, J. Nicolas, et al., Int. J. Pharm. 401 (2010) 103–112. M.I. Papisov, A. Bogdanov, et al., J. Magn. Magn. Mater. 122 (1993) 383–386. H. Lee, E. Lee, et al., J. Am. Chem. Soc. 128 (2006) 7383–7389. M.A. Fortin, R.M. Petoral, et al., Nanotechnology 395501 (2007) 18. A.S. Wadajkar, J.U. Menon, et al., Recent Pat. Biomed. Eng. 6 (2013) 47–57. P. Chattopadhyay, R.B. Gupta, Ind. Eng. Chem. Res. 41 (2002) 6049–6058.

Biomedical Applications of Magnetic Nanomaterials Chapter

[146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192]

12

385

S.K. Sahoo, F. Dilnawaz, et al., International Patent WO2010/134087A1, 2010. H.L. Liu, S.P. Ko, et al., J. Magn. Magn. Mater. 310 (2007) e815–e817. H.Y. Lee, N.H. Lim, et al., J. Biomed. Mater. Res. 79B (2006) 142–150. M. Iijima, Y. Yonemochi, et al., J. Colloid Interface Sci. 298 (2006) 202–208. K.E. Kellar, D.K. Fujii, et al., Magn. Reson. Mater. Phys. Biol. Med. 8 (1999) 207–213. D.K. Kim, M. Mikhaylova, et al., Chem. Mater. 15 (2003) 4343–4351. T. Tegafaw, W. Xu, et al., AIP Adv. 065114 (2016) 6. I.K. Park, C.P. Ng, et al., Biomaterials 29 (2008) 724–732. M. Chastellain, A. Petri, et al., J. Colloid Interface Sci. 278 (2004) 353–360. C. Albornoz, S.E. Jacobo, J. Magn. Magn. Mater. 305 (2006) 12–15. S.A. Corr, S.J. Byrne, et al., J. Am. Chem. Soc. 130 (2008) 4214–4215. J.F. Berret, N. Schonbeck, et al., J. Am. Chem. Soc. 128 (2006) 1755–1761. E.V. Groman, J.C. Bouchard, et al., Bioconjug. Chem. 18 (2007) 1763–1771. G.D. Mendenhall, Y. Geng, et al., J. Colloid Interface Sci. 184 (1996) 519–526. I. Rabias, H. Pratsinis, et al., Biomicrofluidics 044104 (2007) 1. J.A. Park, J.J. Lee, et al., Colloids Surf. A Physicochem. Eng. Asp. 313–314 (2008) 288–291. J.L. Arias, V. Gallardo, et al., J. Biomed. Nanotechnol. 1 (2005) 214–223. S.A. Gomez-Lopera, J.L. Arias, et al., Langmuir 22 (2006) 2816–2821. H. He, H.J. Liu, et al., J. Cent. S. Univ. Technol. 13 (2006) 6–11. J.K. Raty, T. Liimatainen, et al., Gene Ther. 13 (2006) 1440–1446. E. Schellenberger, J. Schnorr, et al., Small 4 (2008) 225–230. S.J. Byrne, S.A. Corr, et al., Chem. Commun. (2004) 2560–2561. D. Farrell, S.A. Majetich, et al., J. Phys. Chem. B 107 (2003) 11022–11030. Q. Sun, Q. Wang, et al., Phys. Rev. Lett. 93 (2004) 186803. R. Shukla, V. Bansal, et al., Langmuir 21 (2005) 10644–10654. K.L. Prime, G.M. Whitesides, Science 252 (1991) 1164. E.E. Carpenter, J. Magn. Magn. Mater. 225 (2001) 17–20. W.L. Zhou, E.E. Carpenter, et al., Eur. Phys. J. D Atom. Mol. Opt. Plasma Phys. 16 (2001) 289–292. T. Hayashi, S. Hirono, et al., Nature 381 (1996) 772–774. S.I. Nikitenko, Y. Koltypin, et al., Angew. Chem. Int. Ed. 40 (2001) 4447–4449. A. Ulman, Chem. Rev. 96 (1996) 1533–1554. A. del Campo, T. Sen, et al., J. Magn. Magn. Mater. 293 (2005) 33–40. M. Yamaura, R.L. Camilo, et al., J. Magn. Magn. Mater. 279 (2004) 210–217. W. Tan, K. Wang, et al., Med. Res. Rev. 24 (2004) 621–638. D.B. Tada, L.L.R. Vono, et al., Langmuir 23 (2007) 8194–8199. Y. Lu, Y. Yin, et al., Nano Lett. 2 (2002) 183–186. T. Sen, A. Sebastianelli, et al., J. Am. Chem. Soc. 128 (2006) 7130–7131. Y. Deng, D. Qi, et al., J. Am. Chem. Soc. 130 (2008) 28–29. S. Peng, C. Wang, et al., J. Am. Chem. Soc. 128 (2006) 10676–10677. Y. Qiang, J. Antony, et al., J. Nanopart. Res. 8 (2006) 489–496. E. Popovici, F. Dumitrache, et al., Appl. Surf. Sci. 254 (2007) 1048–1052. C.T. Chen, Y.C. Chen, Anal. Chem. 77 (2005) 5912–5919. C.Y. Lo, W.Y. Chen, et al., J. Proteome Res. 6 (2007) 887–893. C.T. Chen, Y.C. Chen, J. Mass Spectrom. 43 (2008) 538–541. C.T. Chen, W.Y. Chen, et al., J. Proteome Res. 6 (2007) 316–325. J.C. Liu, P.J. Tsai, et al., Anal. Chem. 80 (2008) 5425–5432. L. Sun, C. Zhang, et al., Anal. Chim. Acta 638 (2009) 162–168.

386 Applications of Nanomaterials [193] [194] [195] [196] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] [210] [211] [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] [227] [228] [229] [230] [231] [232] [233] [234] [235] [236] [237] [238] [239] [240]

M. Arruebo, R. Fernandez-Pacheco, et al., Nanotechnology 17 (2006) 4057. P. Tartaj, T. Gonzalez-Carreno, et al., Adv. Mater. 13 (2001) 1620–1624. G. Carja, H. Chiriac, et al., J. Magn. Magn. Mater. 311 (2007) 26–30. M. Arruebo, M. Galan, et al., Chem. Mater. 18 (2006) 1911–1919. P. Tartaj, T. Gonzalez-Carreno, et al., Langmuir 18 (2002) 4556–4558. L. Faucher, M. Tremblay, et al., ACS Appl. Mater. Interfaces 4 (2012) 4506–4515. R. Bazak, M. Houri, et al., Mol. Clin. Oncol. 2 (2014) 904–908. R. Bazak, M. Houri, et al., J. Cancer Res. Clin. Oncol. 141 (2015) 769–784. R. Weissleder, A. Bogdanov, et al., Magn. Reson. Q. 8 (1992) 55–63. P. Couvreur, C. Vauthier, Pharm. Res. 23 (2006) 1417–1450. B. Vandewalle, A.M. Granier, et al., J. Cancer Res. Clin. Oncol. 110 (1985) 71–76. A.K. Gupta, A.S.G. Curtis, Biomaterials 25 (2004) 3029–3040. L. Debelle, A.M. Tamburro, Int. J. Biochem. Cell Biol. 31 (1999) 261–272. M.E. Baker, FEBS Lett. 439 (1998) 9–12. E.A. Schellenberger, A. Bogdanov Jr., et al., Mol. Imaging 1 (2002) 102–107. J.A. Varner, D.A. Cheresh, Curr. Opin. Cell Biol. 8 (1996) 724–730. M. Lewin, N. Carlesso, et al., Nat. Biotechnol. 18 (2000) 410–414. L. Josephson, C.H. Tung, et al., Bioconjug. Chem. 10 (1999) 186–191. O.C. Farokhzad, S. Jon, et al., Cancer Res. 64 (2004) 7668. J.E. Smith, C.D. Medley, et al., Anal. Chem. 79 (2007) 3075–3082. M.V. Yigit, D. Mazumdar, et al., Bioconjug. Chem. 19 (2008) 412–417. M.V. Yigit, D. Mazumdar, et al., ChemBioChem 8 (2007) 1675–1678. J.K. Herr, J.E. Smith, et al., Anal. Chem. 78 (2006) 2918–2924. S. Goodall, M.L. Jones, et al., J. Chem. Technol. Biotechnol. 90 (2015) 1169–1176. A. Younes, A.K. Gopal, et al., JCO 30 (2012) 2183–2189. A. Quintana, E. Raczka, et al., Pharm. Res. 19 (2002) 1310–1316. R. Weissleder, K. Kelly, et al., Nat. Biotechnol. 23 (2005) 1418–1423. P.S. Low, W.A. Henne, et al., Acc. Chem. Res. 41 (2008) 120–129. X. Zhao, H. Li, et al., Expert Opin. Drug Deliv. 5 (2008) 309–319. R. Banerjee, P. Tyagi, et al., Int. J. Cancer 112 (2004) 693–700. A.D. Friedman, S.E. Claypool, et al., Curr. Pharm. Des. 19 (2013) 6315–6329. J. Wu, M.H. Nantz, et al., Front. Biosci. 7 (2002) d717–d725. N. Schleich, C. Po, et al., J. Control. Release 194 (2014) 82–91. Y. Zhang, N. Kohler, et al., Biomaterials 23 (2002) 1553–1561. R. Sinha, G.J. Kim, et al., Mol. Cancer Ther. 5 (2006) 1909. C. Sun, R. Sze, et al., J. Biomed. Mater. Res. A 78A (2006) 550–557. X. Montet, K. Montet-Abou, et al., Neoplasia 8 (2006) 214–222. O. Veiseh, C. Sun, et al., Nano Lett. 5 (2005) 1003–1008. X. Montet, R. Weissleder, et al., Bioconjug. Chem. 17 (2006) 905–911. S. Boutry, S. Laurent, et al., Contrast Media Mol. Imaging 1 (2006) 15–22. J.H. Park, G. von Maltzahn, et al., Adv. Mater. 20 (2008) 1630–1635. J. Gunn, H. Wallen, et al., Small 4 (2008) 712–715. F.Q. Hu, L. Wei, et al., Adv. Mater. 18 (2006) 2553–2556. Y.M. Huh, Y.W. Jun, et al., J. Am. Chem. Soc. 127 (2005) 12387–12391. D. Artemov, N. Mori, et al., Magn. Reson. Med. 49 (2003) 403–408. C. Sun, O. Veiseh, et al., Small 4 (2008) 372–379. G. Huang, J. Diakur, et al., Int. J. Pharm. 360 (2008) 197–203. H. Hu, A. Dai, et al., Nano 5 (2013) 10447–10454.

Biomedical Applications of Magnetic Nanomaterials Chapter

[241] [242] [243] [244] [245] [246] [247] [248] [249] [250] [251] [252] [253] [254] [255] [256] [257] [258] [259] [260] [261] [262] [263] [264] [265] [266] [267] [268] [269] [270] [271] [272] [273] [274] [275] [276] [277] [278] [279] [280] [281] [282] [283] [284] [285] [286] [287] [288]

12

C.F. Chan, M.K. Tsang, et al., J. Mater. Chem. B 2 (2014) 84–91. B. Sumer, J. Gao, Nanomedicine 3 (2008) 137–140. J.R. McCarthy, Nanomedicine 4 (2009) 693–695. J.R. McCarthy, Adv. Drug Deliv. Rev. 62 (2010) 1023–1030. C. Fang, M. Zhang, J. Control. Release 146 (2010) 2–5. J.M. Idee, S. Louguet, et al., Quant. Imaging Med. Surg. 3 (2013) 292–297. N. Ahmed, H. Fessi, et al., Drug Discov. Today 17 (2012) 928–934. G. Bao, S. Mitragotri, et al., Annu. Rev. Biomed. Eng. 15 (2013) 253–282. Q.A. Pankhurst, J. Connolly, et al., J. Phys. D. Appl. Phys. 36 (2003) R167. R.K. Jain, Adv. Drug Deliv. Rev. 46 (2001) 149–168. X.H. Peng, X. Qian, et al., Int. J. Nanomedicine 3 (2008) 311–321. S. Karthikeyan, H. Hossein, et al., Curr. Nanosci. 5 (2009) 135–140. C. Alexiou, W. Arnold, et al., Cancer Res. 60 (2000) 6641. J. Huang, Y. Li, et al., Adv. Funct. Mater. 26 (2016) 3818–3836. J.S. Ross, J.A. Fletcher, et al., Mol. Cell. Proteomics 3 (2004) 379. T.J. Chen, T.H. Cheng, et al., JBIC J. Biol. Inorg. Chem. 14 (2008) 253. H. Zhou, W. Qian, et al., ACS Nano 9 (2015) 7976–7991. N. Kohler, C. Sun, et al., Small 2 (2006) 785–792. S.E. Lupold, B.J. Hicke, et al., Cancer Res. 62 (2002) 4029. A. Toma, E. Otsuji, et al., Br. J. Cancer 93 (2005) 131–136. K.J. Widder, R.M. Morris, et al., Eur. J. Cancer Clin. Oncol. 19 (1983) 135. A.S. Lubbe, C. Bergemann, et al., J. Magn. Magn. Mater. 194 (1999) 149–155. S.K. Pulfer, S.L. Ciccotto, et al., J. Neuro-Oncol. 41 (1999) 99. S.C. Goodwin, C.A. Bittner, et al., Toxicol. Sci. 60 (2001) 177. S. Goodwin, C. Peterson, et al., J. Magn. Magn. Mater. 194 (1999) 132–139. T.K. Jain, M.A. Morales, et al., Mol. Pharm. 2 (2005) 194–205. K. Schulze, A. Koch, et al., J. Magn. Magn. Mater. 293 (2005) 419–432. N. Kohler, C. Sun, et al., Langmuir 21 (2005) 8858–8864. A.S. Lubbe, C. Bergemann, et al., Cancer Res. 56 (1996) 4694. A.S. Lubbe, C. Bergemann, et al., Cancer Res. 56 (1996) 4686. M.W. Wilson, R.K. Kerlan, et al., Radiology 230 (2004) 287. R. Hiergeist, W. Andra, et al., J. Magn. Magn. Mater. 201 (1999) 420–422. S. Mornet, S. Vasseur, et al., Prog. Solid State Chem. 34 (2006) 237–247. J.P. Fortin, F. Gazeau, et al., Eur. Biophys. J. 37 (2008) 223–228. C.B. Catherine, J. Phys. D. Appl. Phys. 42 (2009) 224003. I. Brigger, C. Dubernet, et al., Adv. Drug Deliv. Rev. 54 (2002) 631–651. D. Bahadur, J. Giri, Sadhana 28 (2003) 639–656. A. Ito, K. Ino, et al., Biomaterials 26 (2005) 6185–6193. A. Ito, M.F. Shinkai, et al., Cancer Gene Ther. 8 (2001) 649–654. C.S.S.R. Kumar, F. Mohammad, Adv. Drug Deliv. Rev. 63 (2011) 789–808. R.K. Gilchrist, R. Medal, et al., Ann. Surg. 146 (1957) 596–606. M. Mitsumori, M. Hiraoka, et al., Hepato-Gastroenterology 43 (1996) 1431–1437. A. Ito, K. Tanaka, et al., J. Biosci. Bioeng. 96 (2003) 364–369. C.L. Dennis, A.J. Jackson, et al., J. Phys. D. Appl. Phys. 134020 (2008) 41. N. Kawai, M. Futakuchi, et al., Prostate 68 (2008) 784. M. Levy, C. Wilhelm, et al., J. Phys. Condens. Matter 20 (2008) 204133. M.S. Martina, C. Wilhelm, et al., Biomaterials 29 (2008) 4137–4145. P. Pradhan, J. Giri, et al., J. Magn. Magn. Mater. 311 (2007) 282–287.

387

388 Applications of Nanomaterials [289] [290] [291] [292] [293] [294] [295] [296] [297] [298] [299] [300] [301] [302] [303] [304] [305] [306] [307] [308] [309] [310] [311] [312] [313] [314] [315] [316] [317] [318] [319] [320] [321] [322] [323] [324] [325] [326] [327] [328] [329] [330] [331] [332] [333] [334] [335]

V.A. Atsarkin, L.V. Levkin, et al., Int. J. Hyperth. 25 (2009) 240–247. O. Kaman, E. Pollert, et al., Nanotechnology 275610 (2009) 20. P. Pradhan, J. Giri, et al., J. Biomed. Mater. Res. 81B (2007) 12–22. D.H. Kim, Y.T. Thai, et al., IEEE Trans. Magn. 45 (2009) 64–70. S. Bae, S.W. Lee, Appl. Phys. Lett. 89 (2006) 252503. D.H. Kim, S.H. Lee, et al., J. Magn. Magn. Mater. 293 (2005) 320–327. H. Nojima, S. Ge, et al., J. Appl. Phys. 107 (2010) 09B320. K. Maier-Hauff, F. Ulrich, et al., J. Neuro-Oncol. 103 (2011) 317–324. K. Maier-Hauff, R. Rothe, et al., J. Neuro-Oncol. 81 (2007) 53–60. A. Jordan, R. Scholz, et al., J. Neuro-Oncol. 78 (2006) 7–14. F.K.H. van Landeghem, K. Maier-Hauff, et al., Biomaterials 30 (2009) 52–57. M. Johannsen, U. Gneveckow, et al., Eur. Urol. 52 (2007) 1653–1662. P. Wust, U. Gneveckow, et al., Int. J. Hyperth. 22 (2006) 673–685. D.H. Kim, K.N. Kim, et al., J. Biomed. Mater. Res. A 88A (2009) 1–11. S.J. DeNardo, G.L. DeNardo, et al., Clin. Cancer Res. 11 (2005) 7087s. A. Natarajan, C. Gruettner, et al., Bioconjug. Chem. 19 (2008) 1211–1218. J. Alonso, H. Khurshid, et al., J. Appl. Phys. 083904 (2016) 119. M. Shinkai, M. Suzuki, et al., Biotechnol. Appl. Biochem. 21 (1995) 125–137. F. Sonvico, S.P. Mornet, et al., Bioconjug. Chem. 16 (2005) 1181–1188. R. Rastogi, N. Gulati, et al., Colloids Surf. B: Biointerfaces 82 (2011) 160–167. A. Ito, Y. Kuga, et al., Cancer Lett. 212 (2004) 167–175. J. Kost, J. Wolfrum, et al., J. Biomed. Mater. Res. 21 (1987) 1367. E.R. Edelman, J. Kost, et al., J. Biomed. Mater. Res. 19 (1985) 67. K. Hayashi, K. Ono, et al., ACS Appl. Mater. Interfaces 2 (2010) 1903–1911. M. Babincova, V. Altanerova, et al., IEEE Trans. Nanobioscience 7 (2008) 15–19. K.L. Ang, S. Venkatraman, et al., Mater. Sci. Eng. C 27 (2007) 347–351. K. Hayashi, M. Nakamura, et al., Theranostics 4 (2014) 834–844. W.F. Anderson, Science 226 (1984) 401–409. R.M. Blaese, Pediatr. Res. 33 (1993) S49–S55. G.U. Dachs, G.J. Dougherty, et al., Oncol. Res. Featur. Preclin. Clin. Cancer Ther. 9 (1997) 313–325. T. Friedmann, R. Roblin, Science 175 (1972) 949–955. D. Kerr, Nat. Rev. Cancer 3 (2003) 615–622. S.D. Li, L. Huang, Gene Ther. 13 (2006) 1313–1319. L.L. Nielsen, D.C. Maneval, Cancer Gene Ther. 5 (1997) 52–63. I.M. Verma, N. Somia, Nature 389 (1997) 239–242. Y.K. Oh, T.G. Park, Adv. Drug Deliv. Rev. 61 (2009) 850–862. H. Shen, T. Sun, et al., Cancer Gene Ther. 19 (2012) 367–373. J.M. Lee, T.J. Yoon, et al., Biomed. Res. Int. 2013 (2013). Y. Fujita, K. Kuwano, et al., Int. J. Mol. Sci. 16 (2015) 5254–5270. M.A. Behlke, Mol. Ther. 13 (2006) 644–670. S. Sharma, Adv. Life Sci. 3 (2014) 58–64. C. Plank, O. Zelphati, et al., Adv. Drug Deliv. Rev. 63 (2011) 1300–1331. A. Fouriki, N. Farrow, et al., Nano Rev. Exp. 1 (2010). S.C. McBain, H.H. Yiu, et al., Int. J. Nanomedicine 3 (2008) 169. J. Dobson, Gene Ther. 13 (2006) 283–287. Z. Medarova, W. Pham, et al., Nat. Med. 13 (2007) 372–377. M. Pickard, D. Chari, Nanomedicine 5 (2010) 217–232.

Biomedical Applications of Magnetic Nanomaterials Chapter

12

389

[336] IBA Solutions for Life Sciences, https://web.archive.org/web/20120223012449/http://www. iba-go.com/naps/naps_fr02_04.html, 2017. [337] E.T. Ahrens, J.W.M. Bulte, Nat. Rev. Immunol. 13 (2013) 755–763. [338] J.V. Jokerst, S.S. Gambhir, Acc. Chem. Res. 44 (2011) 1050–1060. [339] T.F. Massoud, S.S. Gambhir, Genes Dev. 17 (2003) 545–580. [340] J.K. Willmann, N. van Bruggen, et al., Nat. Rev. Drug Discov. 7 (2008) 591–607. [341] L. Cheng, K. Yang, et al., Angew. Chem. Int. Ed. 50 (2011) 7385–7390. [342] E.S. Shibu, K. Ono, et al., ACS Nano 7 (2013) 9851–9859. [343] H. Lee, M.K. Yu, et al., J. Am. Chem. Soc. 129 (2007) 12739–12745. [344] L. Josephson, M.F. Kircher, et al., Bioconjug. Chem. 13 (2002) 554–560. [345] J.H. Lee, Y.W. Jun, et al., Angew. Chem. Int. Ed. 45 (2006) 8160–8162. [346] O. Veiseh, C. Sun, et al., Cancer Res. 69 (2009) 6200–6207. [347] H. Ow, D.R. Larson, et al., Nano Lett. 5 (2005) 113–117. [348] F. Chen, P.A. Ellison, et al., Angew. Chem. Int. Ed. Eng. 52 (2013) 10. [349] R. Torres Martin de Rosales, R. Tavare, et al., Angew. Chem. Int. Ed. Eng. 50 (2011) 5509–5513. [350] H.Y. Lee, Z. Li, et al., J. Nucl. Med. 49 (2008) 1371–1379. [351] L. Sandiford, A. Phinikaridou, et al., ACS Nano 7 (2013) 500–512. [352] L. Frullano, C. Catana, et al., Angew. Chem. Int. Ed. 49 (2010) 2382–2384. [353] C. JS, J.-C. Park, et al., Angew. Chem. Int. Ed. 47 (2008) 6259–6262. [354] R. Misri, D. Meier, et al., Nanomed. Nanotechnol. Biol. Med. 8 (2012) 1007–1016. [355] R. Madru, P. Kjellman, et al., J. Nucl. Med. 53 (2012) 459–463. [356] I. Hizoh, C. Haller, Investig. Radiol. 37 (2002) 428. [357] D. Kim, S. Park, et al., J. Am. Chem. Soc. 129 (2007) 7661–7665. [358] C. Alric, J. Taleb, et al., J. Am. Chem. Soc. 130 (2008) 5908–5915. [359] D.K. Kim, J.W. Kim, et al., Bull. Kor. Chem. Soc. 30 (2009) 1855. [360] D. Kim, M.K. Yu, et al., Nanotechnology 155101 (2011) 22. [361] J. Xie, K. Chen, et al., Biomaterials 31 (2010) 3016–3022. [362] J. Zhou, Z. Lu, et al., Biomaterials 35 (2014) 368–377. [363] M. Nahrendorf, H. Zhang, et al., Circulation 117 (2008) 379–387. [364] T.H. Shin, Y. Choi, et al., Chem. Soc. Rev. 44 (2015) 4501–4516. [365] M. Arruebo, R. Fernandez-Pacheco, et al., Nano Today 2 (2007) 22–32. [366] T. Neuberger, B. Schopf, et al., J. Magn. Magn. Mater. 293 (2005) 483–496. [367] N. Wang, J.P. Butler, et al., Science 260 (1993) 1124. [368] B. Fabry, G.N. Maksym, et al., J. Magn. Magn. Mater. 194 (1999) 120–125. [369] B. Fabry, G.N. Maksym, et al., Phys. Rev. Lett. 148102 (2001) 87. [370] A.R. Bausch, W. Muller, et al., Biophys. J. 76 (1999) 573–579. [371] S.H. Cartmell, S. Hughes, et al., Proceedings of the IEEE-EMBS Special Topic Conference on Molecular, Cellular and Tissue Engineering, 2002, pp. 87–88. [372] A. Ito, H. Honda, Magnetic Nanoparticles for Tissue Engineering, in: Nanotechnologies for the Life Sciences, Wiley-VCH Verlag GmbH & Co. KGaA, New Jersey, 2007. [373] P.A. Liberti, C.G. Rao, et al., J. Magn. Magn. Mater. 225 (2001) 301–307. [374] J.M. Perez, L. Josephson, et al., Nat. Biotechnol. 20 (2002) 816–820. [375] J.M. Perez, T. O’Loughin, et al., J. Am. Chem. Soc. 124 (2002) 2856–2857. [376] J.B. Haun, T.J. Yoon, et al., WIREs Nanomed. Nanobiotechnol. 2 (2010) 291–304.