Drug Deliv. and Transl. Res. (2012) 2:3–21 DOI 10.1007/s13346-011-0049-8

REVIEW ARTICLE

Magnetic nanoparticles and their applications in image-guided drug delivery Mi Kyung Yu & Jinho Park & Sangyong Jon

Published online: 29 December 2011 # Controlled Release Society 2011

Abstract Magnetic iron oxide nanoparticles have been shown to be suitable for use as theranostic agents owing to their intrinsic diagnostic capabilities in magnetic resonance imaging (MRI) applications, hyperthermia properties, and ability to deliver drugs via magnetic attraction and/or systemic delivery. In addition, surface modifications are easily introduced through conjugation with targeting moieties (e.g., antibodies, peptides, or aptamers), genes, or therapeutic drugs to provide multimodal functionalities. Such valuable characteristics apply to image-guided drug delivery, especially MRI-guided drug delivery—a form of individualized therapy in which imaging methods are used to guide and monitor delivery of therapeutic agents to target tissues. This review summarizes the intrinsic physicochemical properties and pharmacokinetics of magnetic nanoparticles and highlights recent reports describing theranostic systems, including magnetic nanoparticle-based nanoplatforms, and their applications in MRI-guided drug delivery. Keywords Magnetic nanoparticles . Multifunctional nanoparticles . Image-guided drug delivery . Theranostics . Hyperthermia . Magnetic drug targeting

Introduction Magnetic iron oxide nanoparticles (IONPs) are of great interest to researchers owing to their unique physicochemical properties, which offer the potential for revolutionizing current M. K. Yu : J. Park : S. Jon (*) Cell Dynamics Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, 261 Chemdangwagi-ro, Gwangju 500-712, Republic of Korea e-mail: [email protected]

clinical diagnostic and therapeutic techniques. One representative property of these nanoparticles is their enhancement of proton relaxation around disease areas, which enables them to be used as anatomical magnetic resonance imaging (MRI) contrast agents. Superparamagnetic iron oxide nanoparticles (SPIONs) in particular have been widely favored for over two decades because of their non-toxic and biocompatible characteristics. A number of SPIONs, including Lumiren® and Gastromark® for bowel imaging and Endorem® and Feridex IV® for liver/spleen imaging, are currently on the market [1, 2]; Combidex® for lymph node metastasis imaging is in clinical trials [3]. In addition, their reactive surfaces can be readily fabricated with biocompatible coating materials, targeting ligands, and/or therapeutic molecules; thus, this flexibility has led to the use of SPIONs in a variety of biomedical applications [4], including medical imaging [5–8], cell tracking [9, 10], tissue repair [11], and drug delivery [12–14]. In recent years, a tremendous amount of research has been devoted to theranostic nanoplatforms—systems capable of codelivering diagnostic and therapeutic agents. The goal of these research efforts is to provide improved therapeutic protocols that are more effective and less toxic for individual patients and, therefore, more likely to realize the potential of “personalized medicine.” In keeping with this goal, magnetic nanoparticles offer an attractive means for remotely directing therapeutic agents to a disease site while simultaneously visualizing drug distribution and predicting therapeutic responses. This multifunctionality is attributed to the intrinsic diagnostic capabilities of magnetic nanoparticles in MRI applications, their hyperthermia properties, and the ease with which such particles can be fabricated to contain various therapeutic or functional moieties. Importantly, as theranostic agents, multifunctional magnetic nanoparticles incorporating therapeutic drugs can be selectively accumulated at pathological sites in vivo utilizing magnetic attraction and/or systemic delivery via

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enhanced permeability and retention (EPR) effects or active targeting [15–17]. Such design principles apply to imageguided drug delivery, a form of individualized therapy in which imaging methods are used to guide and monitor localized and targeted delivery of therapeutics to their target sites [18]. The goal of this approach is to optimize the therapeutic regimen by validating biodistribution, pharmacokinetics, and pharmacodynamics of drugs using imaging techniques. In this review, we will discuss magnetic nanoparticles as MRI contrast agents and consider their therapeutic applications. We will specifically highlight MRI-guided drug delivery via theranostic systems, including magnetic nanoparticle-based nanoplatforms.

Magnetic iron oxide nanoparticles as MRI contrast agents Physicochemical properties Under a given external magnetic field (B0), proton nuclei align in the B0 direction and start to precess with a net magnetic moment and a Larmor precession frequency [15]. When a resonant radiofrequency pulse is applied to B0, resonant excitation of the magnetic moment precession occurs; upon removal of the radiofrequency pulse, the magnetic moment gradually relaxes to equilibrium. MRI records such relaxation processes and reconstructs them to provide 3-D images of anatomical information in biological tissues. However, the differences in contrast between target disease areas and normal tissues are subtle, and the diagnostic information they provide is imprecise. Magnetic nanoparticles enhance contrast differences through an induced magnetic dipole moment (μ) under an applied B0. When water molecules diffuse around the induced dipole moment, the magnetic relaxation of water protons is dephased and the spin–spin relaxation time (T2) is shortened (Fig. 1) [16]. Such changes result in signal reduction on T2-weighted MRIs, producing negative contrast enhancement. This is particularly true for SPIONs, which have an obligatory crystalline nature and therefore exhibit much greater magnetic dipole moments and magnetic susceptibilities compared with corresponding paramagnetic materials because their entire single-crystal (magnetic domain) aligns with B0 [19]. These properties lead to a rapid dephasing of surrounding protons, making SPIONs efficient MRI contrast agents. Upon removal of B0, individual magnetic domains are free to rotate while exhibiting Brownian motion and become randomly oriented with no magnetic remanence. Also, Brownian forces enable SPIONs to maintain their colloidal stability and avoid self-aggregation, facilitating their use in biomedical applications.

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In general, the degree of T2 contrast enhancement is represented by spin–spin relaxivity, R2 (1/T2), which is proportional to the magnetic moment, so the maximization of magnetic moment during nanoparticle synthesis is important [16]. By controlling characteristics of nanoparticles such as size, shape, composition, and crystalline phase, the magnetic moment can be tuned. Recently, Jun et al. compared mass magnetization values with various-size magnetism-engineered iron oxide nanoparticles [20]. They demonstrated that the smaller the nanoparticles, the weaker their net magnetic moment because of the large contribution of canted magnetic spin states on the surface. The magnetic moment of nanoparticles can also be influenced by doping with magnetically susceptible elements. Typically, magnetic iron oxide nanoparticles are composed of nanocrystalline magnetite (Fe3O4) or maghemite (γFe2O3) coated with a biocompatible polymeric layer. In particular, superparamagnetic iron oxide crystalline structures consist of Fe23+O3M2 + O, where M2+ is a divalent metal ion such as iron, manganese, nickel, cobalt, or magnesium [1]. Superparamagnetism occurs when crystal-containing regions of unpaired spins are sufficiently large that they can be regarded as thermodynamically independent, single-domain particles. Such ferrite nanoparticles possess an inverse spinel crystal structure comprising a close-packed cubic lattice formed by oxygen atoms, with tetrahedral sites occupied by Fe3+ ions and octahedral sites occupied by Fe3+ and Fe2+ ions [17]. Under B0, magnetization arises from electron hopping between Fe3+ and Fe2+ ions at the octahedral sites. To improve magnetic properties for applications in molecular imaging, Lee et al. constructed metal-doped iron oxides by synthesizing MnFe2O4, FeFe2O4, CoFe2O4, and NiFe2O4 [21]. Through a comparison of various metal-doped ferrite nanoparticles, this group has demonstrated that mass magnetization values clearly reflect the magnetic-dopant effect; the value is the highest for MnFe2O4 nanoparticles and gradually decreases for FeFe2O4, CoFe2O4, and NiFe2O4. Pharmacokinetics The pharmacokinetics of magnetic nanoparticles in vivo, described in Fig. 2, determines their diagnostic and therapeutic capabilities. In the bloodstream, a variety of opsonin proteins bind to the surface of nanoparticles, a process known as opsonization. This process makes particles more recognizable to biological defense systems such as the mononuclear phagocytic system (MPS) and the reticuloendothelial system (RES). These phagocytic mechanisms render nanoparticles ineffective by clearing them from the circulation [22]. In addition, the heterogeneity and high ionic strength of blood can cause nanoparticle to aggregate, altering their magnetic properties and inducing pulmonary embolism. Therefore, minimizing protein binding and

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Fig. 1 Illustration of the contrast enhancement of magnetic nanoparticles. Under an external magnetic field, magnetic nanoparticles generate an induced magnetic dipole moment that perturbs the magnetic relaxation of water protons. Such changes result in signal reduction on

T2-weighted MRI and lead to MR contrast enhancement, with darkening of the corresponding section of the image. Water protons influenced by magnetic nanoparticles have relatively short T2 relaxation and produce negative contrast enhancement

increasing the blood circulation half-life are key challenges for developing successful theranostic nanoplatforms [23]. The most commonly used strategy is surface engineering to interfere with the adsorption of opsonin proteins to the nanoparticle surface, yielding “stealth” magnetic nanoparticles that become invisible to the MPS and therefore have an increased likelihood of reaching their target tissues. US Food and Drug Administration-approved poly(ethylene glycol) (PEG) or copolymers containing PEG molecules have been commonly used to fabricate camouflaged nanoparticles. Their biocompatibility, hydrophilicity, absence of immunogenicity, and flexibility in biological fluids confer long-circulating characteristics on the inorganic nanoparticles [24, 25]. Features that

are important in improving the stealth properties of nanoparticles include the chain length, conformation, and density of PEG on the surface of nanoparticles. Dextrans are also widely used surface-shielding materials, and several clinically approved MRI contrast agents are prepared by dextran coating [26–28]. Other polymers, such as polyvinyl alcohol [29], polyvinyl pyrrolidine [30], polyacrylic acid [31], and monomeric species, including bisphosphonates [32], dimercaptosuccinic acid [33], and alkoxysilanes [34], have been evaluated as coating materials for use in preventing nanoparticle agglomeration and enhancing blood circulation time. Recently, a new class of non-biofouling zwitterionic materials (macroscopically neutral with a net zero charge) was

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Fig. 2 Pharmacokinetics of magnetic nanoparticles in vivo. In the bloodstream, numerous opsonin proteins, cells, and salts bind to the surface of nanoparticles, leading to the clearance of nanoparticles by the MPS or RES. Using surface engineering to coat nanoparticles with shielding materials (e.g., PEG) or create a neutral charge minimizes protein binding and particle aggregation, thereby increasing particle half-life in the blood. Particle size also matters. Smaller nanoparticles are subject to rapid renal clearance, whereas larger nanoparticles are

sequestered by phagocytic cells of the liver and spleen. In the tumor tissue, smaller nanoparticles can not only easily pass through the leaky capillary wall but can also be readily washed out into the blood. In contrast, larger nanoparticles not only benefit from a slower migration rate through the interstitial space, allowing greater accumulation, but also show restricted penetration into the tumor mass. Modification of nanoparticles with a targeting ligand may enhance tumor accumulation

developed to impart good colloidal stability to nanoparticles [35]. Zhang et al. developed zwitterionic poly(carboxybetaine methacrylate)-3,4-dihydroxyphenyl-L -alanine-decorated magnetic nanoparticles and demonstrated their reduced macrophage uptake and selectivity toward target cells compared to dextran-coated nanoparticles. [35]. The hydrodynamic size of nanoparticles is closely related to their ability to effectively evade uptake by the MPS and overcome vascular barriers. Circulating MPS eliminates nanoparticles from the bloodstream, transporting them to clearance organs (i.e., liver, spleen, kidneys) and bone marrow, where resident cells capture the nanoparticles prior to degradation [36]. In general, smaller nanoparticles are subject to rapid renal clearance, whereas larger ones are sequestered by phagocytic cells of the liver, spleen, and bone marrow [37]. Arruebo et al. and Neuberger et al. reported that magnetic nanoparticles between 40 and 200 nm are cleared by Kupffer cells in the liver (80%) and spleen (15%), whereas nanoparticles larger than 200 nm are usually filtered by the liver, spleen, and lung; in contrast, nanoparticles up to 20 nm escape from phagocytosis and travel in the bloodstream with a long half-life (∼2 h) [36, 38]. Because normal and cancerous or inflammatory tissues exhibit differences in uptake properties, the clearance of nanoparticles by macrophage cells is a useful diagnostic indicator of liver metastasis [39], splenic lymphoma [40], metastatic lymph node [3], atherosclerosis [41],

glioblastoma [42], and stroke [19]. For lymph node or cerebral imaging, magnetic nanoparticles smaller than 20 nm are favored. On the other hand, magnetic nanoparticles as theranostic platforms require a hydrodynamic size between 20 and 100 nm to ensure a blood-circulating ability sufficient to provide the greatest opportunity to target tumor tissues via EPR effects [43]. Because tumor-associated neovasculature is leaky and the interstitial pressure within a tumor is remarkably high, the penetration of nanoparticles into the tumor mass depends on their size range. Small nanoparticles (20 nm) can easily pass through the leaky capillary wall into the tumor but can also be readily washed out into blood. In contrast, larger nanoparticles (100 nm) may benefit from a slower migration rate through the interstitial space that allows greater accumulation; however, such particles also show restricted penetration into the tumor mass. These results suggest that 20–100 nm is the pharmacokinetically optimal range of nanoparticles for the rational design of in vivo tumor-targeting theranostic agents [44]. It is also possible to enhance the retention of small nanoparticles in the tumor by conjugating targeting ligands on the nanoparticle surface [45]. In addition to hydrodynamic size, the surface charge of nanoparticles is an important determinant of the pharmacokinetic profile in the blood. Typically, charged nanoparticles have a short blood circulation time because of opsonization and subsequent elimination from the circulation, as noted

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above; they may also form aggregates that can cause transient embolism [46]. In particular, positively charged nanoparticles can bind nontargeted cells and cause nonspecific internalization or hemolysis. Thus, neutral nanoparticles are favored for prolonged blood circulation compared to charged nanoparticles. Surface modifications with shielding materials like PEG or zwitterionic molecules, described above, have been shown to act through steric repulsion to reduce the possibility of opsonization. The shape and flexibility of nanoparticles have also been suggested as essential physical parameters, although only a limited number of studies have evaluated the biodistribution of nanoparticles with varying geometries. In one such study, Sailor et al. reported that the in vivo tumor-targeting properties of magnetic nanoworms, elongated nanostructures formed by the assembly of iron oxide cores, were superior to those of nanospheres owing to multivalent interactions between the elongated nanoworms and receptors on the tumor cell surface [47].

MRI-guided drug delivery Image-guided drug delivery, especially MRI-guided drug delivery, enables noninvasive assessment of the biodistribution of theranostic agents, monitoring of drug accumulation and distribution at target tissues, controlled drug delivery, and therapeutic response prediction in real time. Magnetic nanoparticle-based nanoplatforms are highly suitable for providing such important information, thereby substantially contributing to the realization of the potential of personalized medicine. This section discusses the various therapeutic systems, including magnetic nanoparticle-based nanoplatforms, and their applications in MRI-guided drug delivery. Magnetic hyperthermia Hyperthermia in a therapeutic context denotes treatment based on the generation of heat at the disease site. Generally, hyperthermia is performed between 41°C and 46°C, a temperature range in which the functions of many enzymatic proteins in cancer cells are modified, altering cellular differentiation and potentially inducing apoptosis; in contrast, normal cells can survive at these relatively elevated temperatures. [48]. In addition to the noninvasive diagnostic characteristics of magnetic nanoparticles, such particles can produce thermal energy under the influence of an external alternating current magnetic field [49]. The dynamic alignment of magnetic dipoles in a single direction that occurs during exposure to a magnetic field transforms magnetic energy into heat as a result of both relaxation and loss of hysteresis of magnetic nanoparticles [50, 51]. Because magnetic heat induction uses radiofrequency electromagnetic waves, tissue penetration is not

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limiting and energy can be transferred to magnetic nanoparticles located 15 cm inside the body [52]. Importantly, their hyperthermic properties can be utilized for producing a unique drug delivery system. When placed in an oscillating magnetic field, drugs incorporated within magnetic nanoparticle-based theranostic agents or fluorophores bound magnetic nanoparticles through the heat-labile linker exhibit remotely controlled release via on-demand actuation of the thermal energy generation. Derfus et al. demonstrated the ability to remotely trigger the release of biomolecules from magnetic nanoparticles in a model tumor near the posterior mammary fat pad of mice [53]. As shown in Fig. 3a, dextran-coated iron oxide nanoparticles bound to fluorophore-labeled single-stranded DNA via a heat-labile linker were trapped in a matrigel plug and subcutaneously implanted in live mice to form an in vivo tumor tissue model. Upon exposure to a radiofrequency electromagnetic field, fluorescent DNA, as the model drug, diffused out into the surrounding tissue more effectively than did DNA in unexposed controls (Fig. 3b, c). This magnetically stimulated nanoplatform also allowed noninvasive visualization by MRI, as depicted in Fig. 3d, suggesting the potential for MRI-guided, physician-directed remote drug delivery. Thomas et al. designed magnetic-core silica nanoparticles as a new generation, heat-activatable drug delivery system for magnetochemotherapy [54]. As shown in Fig. 4a, these researchers synthesized a mesoporous silica framework and loaded two cargos: zinc-doped iron oxide nanocrystals (ZnNCs), providing hyperthermic capability, and doxorubicin, contributing a cancer-killing property. A nanovalve was assembled onto this silica nanoparticle system by electrostatically binding cucurbit[6]uril with the molecular thread, N-(6-N-aminohexyl)aminomethyltriethoxysilane. The nanovalve remained closed at physiological temperatures and opened upon local heating by magnetic ZnNCs in the presence of an oscillating field. When breast cancer cells (MDA-MB-231) were incubated with doxorubicincontaining magnetic-core silica nanoparticles and exposed to a magnetic field, doxorubicin was released from the silica pores as a result of actuation of the nanovalves and ultimately caused apoptosis, highlighting the merits of this noninvasive, externally controlled, drug-delivering magnetic nanoplatform (Fig. 4b, c). Lee et al. developed exchange-coupled magnetic nanoparticles with high thermal energy transfer capability and demonstrated their in vivo antitumor efficacy [52]. Although magnetic nanoparticles have attracted increasing recent attention for their ability to mediate heat generation, their relatively poor energy conversion efficiencies limit the functionality of the heat induction process, slowing practical applications of the concept [55]. To increase the efficacy of magnetic thermal induction by nanoparticles, Lee et al. designed a core–shell structure of

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Fig. 3 Remotely triggered release from magnetic nanoparticles in vivo. a Magnetic nanoparticles are mixed with matrigel and injected subcutaneously near the posterior mammary fat pad of mice, where they form tumors. Application of an electromagnetic field (EMF) to implants containing nanoparticles with 18-bp tethers results in the

release of model drugs. b Drug penetrates far into the surrounding tissue of EMF-exposed mice c compared to unexposed controls (scale bar0100 μm). d Transverse section of a mouse imaged with a 7-T MRI scanner depicts image contrast due to the presence of nanoparticles (arrow). Reproduced with permission from [53]

nanoparticles with mutual coupling of magnetically hard and soft components. Figure 5a schematically depicts a magnetically coupled binary system (CoFe2O4@MnFe2O4) nanoparticle that shows superior specific loss powers (SLPs), a gauge of conversion efficiency, compared to single-component

magnetic nanoparticles or conventional superparamagnetic nanoparticles. The antitumor effect of hyperthermia treatment with magnetically coupled nanoparticles was tested by exposing nude mice implanted with human U87MG brain cancer cells to alternating current magnetic induction. As shown in

Fig. 4 a Preparation of magnetic-core silica nanoparticles. 1 ZnNCs are synthetically positioned at the 2 core of the mesoporous silica nanoparticles. 3 The base of the molecular machine is then attached to the nanoparticle surface. 4 Drug is loaded into the particle and capped to complete the system. 5 Release can be achieved using remote heating via the introduction of an oscillating magnetic field. b Fluorescence microscopic images of MDA-MB-231 cells exposed to

doxorubicin-containing magnetic-core silica nanoparticles. Color scheme: green fluorescently labeled nanoparticles, red doxorubicin. 1, 2 Nanoparticles containing doxorubicin without magnetic field; 3, 4 nanoparticles without doxorubicin in the presence of a magnetic field; 5, 6 nanoparticles containing doxorubicin with a magnetic field. c Quantitative assessment of cell death with the indicated protocols. Reproduced with permission from [54]

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Fig. 5 a Schematic of a 15-nm CoFe2O4@MnFe2O4 nanoparticle and its SLP value compared with that for each of its components (9 nm CoFe2O4 and 15 nm MnFe2O4). b, c In vivo hyperthermia treatment of cancer. b Nude mice xenografted with cancer cells (U87MG) before treatment (upper row, dotted circle) and 18 days after treatment (lower

row). c Plot of tumor volume (V/Vinitial) versus days after treatment with core–shell nanoparticle hyperthermia, doxorubicin, Feridex hyperthermia, alternating current (a.c.) field only, core–shell nanoparticles only, and in untreated controls. Reproduced with permission from [52]

Fig. 5b, c, tumors were eliminated only in the hyperthermia treatment group with magnetically coupled nanoparticles, and the overall therapeutic outcome was distinctly greater in this group than in the conventional anticancer drug-treated group, indicating the therapeutic potential of this platform in vivo. On the other hand, the MRI technique in combination with local hyperthermia can also directly measure temporal and spatial patterns of the intratumoral distribution of anticancer drugs in animal tumor models. Manganese, a T1 MRI contrast agent that interacts with surrounding water molecules to produce positive contrast enhancement is especially suitable for monitoring drug delivery profiles because its interaction with water differs depending on whether it is present within or outside of water-impermeable vesicles, such as liposomes. Ponce et al. investigated the relationship between MRI-based drug concentrations in the tumor and

those measured by high-performance liquid chromatography (HPLC) or histological fluorescence using lysolipidbased, temperature-sensitive liposomes (LTSL) containing manganese sulfate (MnSO4) and doxorubicin (Dox/MnLTSLs) [56]. At temperatures below the transition temperature (Tg), the relaxivity of Dox/Mn-LTSLs was comparable to that of nonthermosensitive liposomes, but it increased when exposed to local hyperthermia in excess of Tg. These findings imply that the release of contrast agent from LTSLs can be regarded as doxorubicin release, enabling a concept of “drug-dose painting” [57]. As demonstrated in Fig. 6a, LTSLs rapidly released their contents and caused accumulation in tumors upon intravenous administration in rats bearing flank-implanted fibrosarcomas with a central heating catheter. Moreover, the release of MRI-based contrast agent was highly correlated with the results of HPLC- and

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Fig. 6 a The procedure for calculating T1-based drug concentration. 1 An initial (t00 min) raw signal intensity map shows an axial view of a rat bearing a flank-implanted fibrosarcoma (top left) with a central heating catheter (black spot). 2 The initial T1 intensity map is calculated from a series of multiple flip-angle images. 3 The raw signal intensity map at 45 min after injection and content release of LTSLs. 4 The calculated T1 map at 45 min after injection. 5 The calculated doxorubicin concentration (nanograms per milligram) on a pixel-bypixel basis from images 2 and 4. 6 An enlarged image of 5 showing the heterogeneity in drug delivery that can be imaged and quantified by this MRI technique. b Results obtained by HPLC and fluorescence-

validated doxorubicin measurements in each animal. c Visualization of contrast agent release from Dox/Mn-LTSLs under hyperthermia. Top LTSLs administered during steady-state hyperthermia; middle LTSLs administered before hyperthermia; bottom LTSLs administered in two equal doses, half before hyperthermia and the remainder after reaching steady-state hyperthermia. d T1-based mean tumor doxorubicin concentrations after treatment with LTSLs during hyperthermia, shown as a function of the normalized tumor radius for each rat. e Mean doxorubicin concentration profiles for each of the three therapeutic groups as a function of the normalized tumor radius. Reproduced with permission from [56]

fluorescence-validated doxorubicin measurements obtained from each animal (Fig. 6b). With respect to drug-dose painting, three different Dox/Mn-LTSLs plus hyperthermia protocols resulted in obvious differences in drug delivery patterns, as shown in Fig. 6c–e. For instance, LTSLs administered during steady-state hyperthermia resulted in peripheral enhancement, LTSLs administered before hyperthermia caused central enhancement, and LTSLs administered in two equal doses, half before hyperthermia and the remainder after steady-state hyperthermia, resulted in uniform enhancement. These examples convincingly demonstrate the suitability of the MRI-based technique for visualizing and quantifying drug concentration with high temporal and spatial resolution. Similarly, Langereis and colleagues have employed thermosensitive liposomal contrast agents for MRI-guided drug delivery [58]. In this study, the 1H chemical exchange saturation transfer (CEST) agent, Tm(hpdo3a)(H2O), and the 19 F MRI probe, NH4PF6, were coloaded into temperaturesensitive liposomes to provide both chemical shift and MRI contrast enhancement. LipoCEST agents have been utilized to achieve chemical exchange of magnetically labeled water molecules [59], with the enhancement in contrast produced by these agents being determined by the transmembrane water diffusion rate, the amount of intraliposomal water,

and the radiofrequency power. At temperatures below Tg (38°C), the chemical shift agents are released and the lipoCEST enhancement of contrast vanishes. Simultaneously, the 19F MRI probes are freed, causing the appearance of a 19F signal that enables quantification of drug release. The same research group confirmed this MRI-guided monitoring of drug release via encapsulation of both doxorubicin and the MRI contrast agent, Gd(hpdo3a)(H2O), within similar thermosensitive liposomes [60]. The liposomal membrane acted as a diffusion barrier below Tg and modulated water diffusion in the presence of a heating-producing source, thereby generating MRI contrast enhancement and making it possible to image the release of doxorubicin under MRI guidance. Magnetic drug targeting The primary drawback of most chemotherapeutic agents is a lack of selectivity and thus the potential for nonspecific toxicity toward healthy tissues. Magnetic nanoparticles can

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take advantage of an external magnetic field to direct drug molecules to a target site via magnetic attraction [36]. This process is called magnetic targeted carrier (MTC) drug delivery technology. MTC technology utilizes the physical force of a magnetic field rather than a biological mechanism, drawing the MTC drug compound through the arteriole wall into the targeted disease area, resulting in localization and retention of the delivered therapeutic agents at the desired site, even after the magnetic field has been removed. Targeting and prolonged retention of MTC drug compounds at the target site reduces its clearance by the RES and facilitates extravascular uptake [61]. Several points need to be considered for optimization of intratumoral magnetic nanoparticle accumulation: (1) The nanoparticles should be large enough to be attracted by the magnetic field, (2) the strength of the magnetic field gradient should be sufficient to draw magnetic nanoparticles through the endothelial wall of the randomly oriented capillary bed in 3D space of tumors, and (3) the MTC drug complex should deliver a large enough number of drug molecules and release them in a controlled manner around the target area. Alexiou et al. reported the efficacy of magnetic drug targeting of SPION–mitoxantrone (MTX) complexes (∼100 nm in diameter) for the treatment of VX-2 squamous cell carcinoma [61]. The nanoparticles were surrounded by starch polymers to promote stabilization and allow chemoabsorptive binding with cationic MTX. Intratumoral accumulation of intra-arterially infused SPION–MTX (20% and 50%) into rats bearing tumors at the median portion of the hind limb could be visualized by MRI and led to complete tumor remission (1.7 T). The application was well tolerated by the animals, and no signs of toxicity, such as alopecia, ulcers, or muscular atrophy, were observed. In contrast, intra-arterial infusion of the same doses of MTX alone did not reduce tumor volume, and the animals developed metastases and suffered from side effects. These results demonstrate that the combination of intra-arterial infusion of a magnetic nanoparticle–therapeutic drug complex with a magnetic field offers a unique means for treating malignant tumors locoregionally without producing systemic toxicity. The first clinical trials of magnetic drug targeting were conducted by Lübbe et al. [62]. In a previous study, these authors showed that intravenously administered epirubicinbound magnetic fluid (100 nm in diameter) was well tolerated in nude mice implanted with colon adenocarcinoma or with renal cell carcinoma and caused tumor remission following sustained (20 min) direction of a magnetic fluid to the tumor [63]. In this phase I clinical trial, appropriate doses of and tolerance to epirubicin-bound magnetic fluid were determined in patients with advanced and unsuccessfully treated cancers or sarcomas. Fourteen patients received different courses of magnetic drug targeting consisting of infusion of epirubicin-bound magnetic fluid in

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increasing doses from 5 to 100 mg/m2 with magnetic field exposure for 60–120 min. Magnetic fluid could be delivered to tumors in about half of the patients. Organ toxicity did not increase with treatment, but epirubicin-associated toxicities appeared at doses greater than 50 mg/m2. This study showed the potential practicality, safety, and effectiveness of magnetic drug targeting; however, the treatment technology still requires improvement because of the limited reduction in hematological side effects and the variable degrees of magnetite accumulation in the tumor. MTCs loaded with doxorubicin (MTC–DOX) have also been used to treat patients with inoperable hepatocellular carcinoma [64]. A combination of MRI and a conventional angiography system consisting of a 1.5-T short-bore magnet connected to a C-arm angiography unit was used to diagnose tumor area, manipulate the catheter to the hepatic artery, and selectively deliver MTC–DOX to the tumor. In this dual modality system, the MRI component complemented the angiographic component and helped to define tumor size and location before MTC–DOX administration. After MTC– DOX was delivered, MRI enabled immediate intraprocedural evaluation of the location of unaffected tumor, the size of the treated regions, and the extent of affected normal parenchyma. Results of MRI/angiography in patient follow-ups demonstrated a therapeutic effect, suggesting the potential of MRIguided therapeutic agent administration. Recently, Mikhaylov et al. developed a ferri-liposome as an MRI-visible drug delivery system for targeting tumors and their microenvironment under the influence of an external magnet [65]. Ferromagnetic iron oxide (FMIO) nanoparticles were prepared by mechanochemical synthesis [66] and encapsulated in sterically stabilized, PEG-coated liposomes, forming particles with an average diameter of 92.3 nm, measured by dynamic light scattering (Fig. 7a). Because of clustering, the relaxivities of FMIO nanoparticles were several-fold higher than those of a commercially available SPION (Feridex) and the standard gadolinium-based T1 contrast agent (Magnevist). As shown in Fig. 7b, magnetic targeting of ferri-liposomes loaded with luciferase substrate to doubletransgenic FVB.luctg/+;PyMTtg/+ mice resulted in a luminescent signal that was exclusively distributed around the tumor region, demonstrating effective in vivo release of the cargo from the targeted ferri-liposomes. Upon application of a magnetic field, T2-weighted MR images of an MMTV-PyMT tumor-bearing mouse injected with ferri-liposomes indicated a dark area at the tumor tissue, confirming successful tumor targeting of ferri-liposomes and highlighting the possibility of monitoring their distribution by noninvasive MRI technology (Fig. 7c). An in vivo study designed to test inhibition of tumor growth in an orthotopically transplanted mouse mammary tumor model was then performed using ferri-liposomes containing JPM-565, an inhibitor of cysteine cathepsin, which is closely associated with tumor progression (Fig. 7d). As shown

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Fig. 7 a Schematic showing the preparation of ferri-liposomes. b Optical imaging of FVB.luctg/+; PyMTtg/+ mice that have been intraperitoneally administered ferri-liposomes carrying D-luciferin in the presence (targeted FL) and absence (nontargeted FL) of magnet application. c T2-weighted MR images of an MMTV-PyMT transgenic

mouse before and 1 and 48 h after intraperitoneal injection of ferriliposomes followed by 1 h of magnetic field application to the lower right tumor (white arrow). d Schematic showing treatment experimental design. e Tumor volumes measured in the different treatment groups on each treatment day. Reproduced with permission from [65]

in Fig. 7e, mice treated with magnetically targeted JPM-565loaded ferri-liposomes displayed a significant retardation in tumor growth compared with all other treatment groups. Successful cathepsin inhibition was confirmed by a decrease in the cell proliferation marker Ki67 and the translocation of the cell-adhesion protein E-cadherin from the cytosol to the cell surface. Magnetic drug targeting can also be combined with focused ultrasound (FUS) for treating central nervous system (CNS) targets. In general, the blood–brain barrier (BBB) in the CNS excludes larger (>400 Da) molecules from entering the brain parenchyma to protect it from toxic foreign substances, limiting drug delivery across the BBB. Liu et al. designed a combined FUS/magnetic targeted delivery system for reaching the brain across the BBB, both passively and actively, for the treatment of CNS diseases [67]. In this study, noninvasive FUS was used to temporarily disrupt the BBB locally to deliver therapeutic magnetic nanoparticles through EPR effects [68], and an external magnetic force was applied to actively increase the local concentration of magnetic nanoparticles. Iron oxides were encapsulated in poly[aniline-co-N(1-one-butyric acid)] aniline, and the cytotoxic anticancer agent epirubicin was immobilized on the surface of the magnetic nanoparticles via ion interaction. After epirubicin magnetic nanoparticle treatment with combined FUS/MT in a brain tumor animal model, application of magnetic targeting

for 6 h after FUS treatment increased relaxation rates 2.6-fold at the tumor site; in contrast, control animals showed no accumulation of magnetic nanoparticles in T2-weighted MR images (Fig. 8a–c). Transmission electron microscopy (TEM) showed that FUS apparently induced interendothelial clefts with no obvious tight–junctional complexes in tumors (Fig. 8d) and revealed that epirubicin magnetic nanoparticles were taken up by tumor cells and macrophages (Fig. 8e, f). Furthermore, confocal microscopy confirmed that more epirubicin magnetic nanoparticles were deposited at the tumor site than in the contralateral side, consistent with the distribution of magnetic nanoparticle determined by MRI (Fig. 8g, h). Collectively, these results suggest that therapeutic magnetic nanoparticles can be effectively delivered to CNS tumor sites by enhancing BBB permeability with FUS and concurrently applying magnetic targeting, and the deposition of therapeutic magnetic nanoparticles can be monitored and quantified in vivo by MRI. Theranostic platforms A number of theranostic platforms based on magnetic nanoparticles, in addition to magnetic hyperthermia and magnetic drug targeting, have been studied for simultaneous noninvasive detection of disease sites, selective delivery of drug, assessment of drug distribution, and real-time monitoring of

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Fig. 8 In vivo T2-weighted MR images and the corresponding R2 maps of brain tumors without a or with b FUS and magnetic targeting. c Relaxivities measured in tumor regions from control and experimental groups. d–f TEM images of brain tumors showing the presence of magnetic nanoparticles (MNPs) inside opened tight junction structures (TJ) and uptake by tumor cells (TC) and macrophages (M). Numerous caveolae in tumor cells or macrophages indicate apoptosis resulting from

the uptake of epirubicin MNPs. EC endothelial cell. g, h Confocal micrographs of tissue from tumor and contralateral brain regions. Left dark structures in the phase micrographs show MNPs. Right fused fluorescent images indicate the presence of epirubicin (red) and 4′,6-diamidino-2phenylindole-stained nuclei (blue). Arrows indicate capillaries; epirubicin was detected in capillary beds but did not penetrate into the brain parenchyma. Reproduced with permission from [67]

therapeutic responses. The proven ability of these theranostic platforms to promote the accumulation of therapeutic agents around target tumors, either through EPR-mediated passive targeting or specific ligand-mediated active targeting, provides a potent rationale for their continued development. Medarova et al. developed a siRNA-linked magnetic nanoparticle system for in vivo imaging of siRNA delivery and gene silencing in tumors [69]. These researchers synthesized triple-labeled magnetic nanoparticles consisting of a Cy5.5 near-IR fluorescence (NIRF) dye for optical imaging, a myristoylated polyarginine peptide for efficient cytoplasmic delivery and siRNA for specific silencing of the antiapoptotic gene BIRC5, which encodes survivin (Fig. 9a). Systemic administration of MN-NIRF-siSurvivin in nude mice-bearing human colorectal carcinoma tumors caused a significant drop in tumor-associated T2 relaxation times and a distinct, intense fluorescence signal, as determined by in vivo MRI and NIRF imaging, respectively (Fig. 9b). An analysis of survivin silencing by reverse transcription polymerase chain reaction (RT-PCR) indicated that survivin transcript levels in tumors treated with MNNIRF-siSurvivin were considerably lower than those in controls treated with the parental magnetic nanoparticles or mismatched control siRNAs (Fig. 9c). Importantly, survivin knockdown was accompanied by a noticeable increase in tumor-associated levels of apoptosis and necrosis compared

to those in controls (Fig. 9d, e), suggesting the potential for simultaneous delivery and detection of siRNA-based therapeutic agents in vivo. The same research group demonstrated the therapeutic efficacy of the siRNA-linked magnetic nanoparticle system [70]. Using a breast tumor-targeting nanodrug (MN-EPPT-siBIRC5) employing an EPPT peptide to specifically bind the uMUC-1 antigen, present in >90% of human breast adenocarcinomas, these researchers showed that breast tumor-bearing animals treated with the nanodrug exhibited a 2-fold decrease in tumor growth rate compared to those treated with the mismatch control (Fig. 9f). Hematoxylin and eosin (H&E) staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays further confirmed the presence of substantial levels of both necrosis and apoptosis in nanodrug-treated tumors (Fig. 9g), suggesting the potential of this nanoplatform for reporting on drug accumulation around tumor tissue, guiding the selection of an optimal treatment regime, and quantifying tumor volume over the course of treatment as an indicator of therapeutic response. In a similar manner, a magnetic nanoparticle-based polymeric vector system utilizing an MRI-visible gene carrier was developed by Chen et al. [71]. These researchers synthesized an anti-CD3 single-chain antibody (scAbCD3)-conjugated, poly(ethylene glycol)-grafted, polyethyleneimine (PEG-gPEI)-coated SPION vector for T lymphocyte targeting and

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Fig. 9 a Schematic of siRNA-linked magnetic nanoparticles. b In vivo MR images (top) and optical images (bottom) of mice-bearing human colorectal adenocarcinoma (arrows) injected with MN-NIRFsiSurvivin. c Quantitative RT-PCR analysis of survivin expression in tumors after the indicated treatments. d Fluorescence images of apoptotic nuclei (green) in tumors after the indicated treatments. e H&E

staining of frozen tumor sections revealed considerable eosinophilic areas of tumor necrosis (N) in tumors and purple hematoxyphilic regions (V) indicating viable tumor tissues. f Relative tumor volumes with the indicated treatments. g H&E and TUNEL staining of tumor tissue from mice treated with MN-EPPT-siBIRC5 or MN-EPPTsiSCR. Reproduced with permission from [69, 70]

therapeutic gene condensing. The final T cell targeting polyplex (scAbCD3-PEG-g-PEI-SPION/DNA) was prepared by incorporating a diacylglycerol kinase (DGKα) gene, an inhibitor of T cell receptor (TCR) signaling [72]. T2weighted MRI indicated that the polyplexes were efficiently taken up by target T cells (HB8521) via CD3 receptor-mediated endocytosis. Furthermore, a quantitative flow cytometric analysis demonstrated the superior gene transfection efficiency of CD3-targeted polyplexes compared to nontargeted polyplexes, despite the general difficulty of transfecting T cells. DGKα transfection into HB8521 cells resulted in lower levels of cell proliferation and IL-2 expression in response to immune stimulation, suggesting that an MRI-visible, magnetic nanoparticle-based vector system can dampen TCR-induced diacylglycerol signaling. Considerable recent effort has been devoted to the development of magnetic nanoparticle-based theranostic systems that incorporate chemotherapeutic agents. Ling et al. designed prostate tumor-targeted, single-chain anti-prostate stem cell antigen (PSCA) antibody (scAbPSCA)-immobilized, multifunctional polymeric vesicles entrapping both SPIONs and docetaxel (Dtxl) [73]. Amine-terminated poly(lactic-coglycolic) acid was used for loading these diagnostic and therapeutic molecules and for conjugating with a prostate

tumor-targeting antibody. The drug encapsulation efficiency was high (6.02 wt.%) because Dtxl molecules partitioned into the oleic acid/oleylamine shell of the SPION via hydrophobic interactions, thereby providing a controlled drug-release profile. In T2-weighted MRI, PC3 cells incubated with scAbPSCADtxl/SPION produced distinct darkened regions compared to those incubated with polymeric vesicles without scAbPSCA or the commercial contrast agent, Endorem® (Guerbet, France). In addition, the multifunctional polymeric vesicles exerted antiproliferative effects on prostate cancer cells, indicating that scAbPSCA -Dtxl/SPION could be used as prostatetargeted theranostic agent. Yu et al. reported thermally cross-linked (TCL)-SPIONs as drug delivery carriers for combined cancer imaging and therapy (Fig. 10a–c) [74]. These researchers synthesized TCL-SPIONs that combined a diagnostic MRI property (iron oxide functionality), an antibiofouling property (PEG functionality), in vivo stability (cross-linked polymeric shell functionality), and a drug-binding property (carboxyl functionality) and then incorporated doxorubicin onto the nanoparticles via ionic interactions (Fig. 10a). Doxorubicin binding was monitored by fluorescence quenching of doxorubicin upon addition of increasing amounts of TCLSPIONs, which occurred as a result of electronic energy

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Fig. 10 a Formation of Dox@TCL-SPIONs. b Fluorescence spectra of Dox solutions with increasing amounts of TCL-SPIONs. c Antitumor efficacy of Dox@TCL-SPION in an LLC allograft animal model. Top excised tumors from mice euthanized after 19 days of the following treatments: 1 control, 2 TCL-SPION (12.5 mg Fe/kg), 3 Dox (0.64 mg/kg), 4 Dox (5 mg/kg), 5 Dox@TCL-SPION (12.5 mg Fe/kg, 0.64 mg Dox/kg). Bottom inhibition of tumor growth was evident in each treatment group. d Schematic depicting the preparation of Dox@ Apt-hybr-TCL-SPIONs. e Dox-release profiles for Dox@Apt-hybrTCL-SPIONs measured in Ham’s F12K media containing 10% fetal

bovine serum and in rat plasma. f T2-weighted MR images of LNCaP and PC3 cells obtained after incubation with Apt-hybr-TCL-SPIONs (white bar) or scrApt-hybr-TCL-SPIONs (black bar). g T2-weighted fast-spin echo images at the level of the LNCaP tumor on the right side of the mouse taken at 0, 2, 24, and 48 h after injection of the nanoparticles. The dashed circle indicates the xenografted tumor region. h Relative signal enhancement (RSE; in percent) at the tumor areas of nanoparticle-treated mice were recorded from T2-weighted images as a function of time. Reproduced with permission from [74, 76]

transfer (Fig. 10b) [75]. In vivo MRI and tumor growth inhibition studies demonstrated that the excellent passive tumor-targeting efficiency of TCL-SPIONs allowed simultaneous detection of the tumor by MRI and confirmation of the delivery of sufficient amounts of chemotherapeutic agent. The results of these studies suggested that questions pertaining to tumor location, proper delivery of drugs to the tumor site, and efficacy of the therapeutic response around the tumor could all be answered using the drug-delivering magnetic nanoparticle (DMNP) system. The same research group developed prostate cancer-targeted multifunctional nanotheranostics based on TCL-SPIONs [76]. For prostate cancer targeting, they employed a prostate-specific membrane antigen (PSMA) aptamer on the surface of the TCLSPION. As shown in Fig. 10d, amine-terminated

oligonucleotides (ONTs; 5′-[TCG]7-3′) were first immobilized on the carboxyl-containing TCL-SPION, after which elongated PSMA aptamers containing a sequence complementary to ONTs were conjugated by hybridization to produce the Apt-hybr-TCL-SPION. The resulting CG-rich duplex regions in the Apt-hybr-TCL-SPION enabled loading of multiple doxorubicin molecules onto the nanoparticles. An analysis of Dox@Apt-hybr-TCL-SPION drug-release profiles in plasma showed that doxorubicin was released in a quite steady and controlled manner, despite the degradation of nucleotides by serum nucleases (Fig. 10e). In vitro and in vivo MRI revealed the selectivity of Apt-hybr-TCL-SPIONs for target prostate cells or tumors compared to mismatched control-containing SPIONs (Fig. 10f–h). Notably, the in vivo signal drop in Apt-hybr-TCL-SPION-treated mice indicated

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prolonged binding up to 48 h, demonstrating that PSMA aptamer-mediated targeting was stable in vivo. Therapeutic efficacy studies confirmed both selectivity and stable drug delivery. A hypoxic metabolic state creates acidic conditions around a tumor (pH 5.8–7.1) that can provide a triggering signal for the release of drug molecules in cancer-targeted theranostic nanoplatforms. Lim et al. reported HER2/neu antibody-modified, pH-sensitive (HER)-DMNPs as a prototype of molecular imaging-guided theranostic agents for effective cancer therapy [77]. These nanoplatforms were composed of α-pyrenyl-ω-carboxyl poly(ethylene glycol) that encapsulated MnFe2O4 nanocrystals and doxorubicin through the nanoemulsion method. At neutral pH, doxorubicin molecules bind the pyrene groups in the nanoparticles through strong π–π interactions but are released under acidic conditions owing to the protonation of doxorubicin. Initially, these researchers determined the minimal time period (72 h) required for the effective discharge of deliverable drug using in vivo MRI and performed tumor growth inhibition studies using this therapeutic dosing schedule (i.e., every 72 h). Treatment of NIH3T6.7 (HER2/neu+) tumor-bearing mice with HER-DMNPs caused substantial tumor regression compared to other groups without producing side effects, demonstrating the potency and therapeutic effectiveness of the dose delivery strategy as well as its exceptional tumor-targeting ability. T2weighted MRI was also utilized at various time intervals to confirm the inhibition of tumor growth in response to HERDMNPs and demonstrate the progressive accumulation of HER-DMNPs in the tumors. Photodynamic therapy (PDT) involves the uptake of a photosensitizer by cancer cells followed by photoirradiation to activate the sensitizer. PDT is an interesting technology for the treatment of malignant tumors because it offers localized treatment and significantly improved survival [78, 80]; however, system administration carries the

drawback of prolonged cutaneous photosensitization. Targeted delivery of nanoparticles encapsulating photodynamic agents is one potential approach for overcoming the shortcomings of systemic therapy. Reddy et al. developed brain tumor-targeted, multifunctional polymeric nanoparticles carrying both photosensitizers and MRI contrast agents for targeted therapy and monitoring of therapeutic responses [81]. As shown in Fig. 11a, these researchers prepared photofrin- and iron oxide-encapsulated polyacrylamide nanoparticles and conjugated PEG for stability and F3 peptides for tumor vasculature targeting. Figure 11b–f shows T2-weighted MRI with color overlays representing the apparent diffusion coefficient values for tumors in a representative animal from each group 8 days after various nanoparticle treatments. In this study, the changes in tumor diffusion values by PDT were quantified using diffusion MRI, as previously reported [82]. As shown in MR images, the animal treated with F3-targeted nanoparticles (Fig. 11f) exhibited the largest increase in tumor diffusion values (∼40%). Notably, the same F3-targeted nanoparticle-treated animal showed a high diffusion value indicative of a cystic cavity at 40 days after treatment (Fig. 11g). A quantitative analysis of these data showed that treatment with F3-targeted nanoparticles correlated with the longest animal survival times compared to other treatment groups (Fig. 11h), demonstrating the versatility and efficacy of the brain tumor-targeted, multifunctional nanoparticle system. Hadjipanayis et al. utilized MRI-guided convectionenhanced delivery (CED) for glioblastoma targeting and treatment [83]. CED is a method of continuous injection under a pressure gradient formed by the fluid containing the therapeutic agent [84]. Because CED prevents nanoparticles from becoming entrapped in the liver, spleen, or circulating macrophages after systemic administration, it has been increasingly used to deliver therapeutic agents for the treatment of malignant gliomas [85, 86]. Hadjipanayis et al.

Fig. 11 a Schematic representation of F3-targeted nanoparticles encapsulating photofrin and MRI contrast agents. T2-weighted MR images at day 8 after treatment obtained from b a representative control 9 L tumor and tumors c treated with laser light only, d administered photofrin (i.v.) and treated with laser light, e administered nontargeted nanoparticles containing photofrin (i.v.) and treated with laser light, and f administered targeted nanoparticles containing photofrin (i.v.)

and treated with laser light. The image shown in g is from the same F3targeted nanoparticle-treated tumor shown in f, but at day 40 after treatment. The color diffusion maps overlaid on T2-weighted images represent the apparent diffusion coefficient (ADC) distribution in each tumor slice shown. h Mean peak percentage change in tumor ADC values for each of the experimental groups. Reproduced with permission from [81]

Drug Deliv. and Transl. Res. (2012) 2:3–21

17

synthesized IONPs containing an antibody against an epidermal growth factor receptor (EGFR) deletion mutant (EGFRvIIIAb-IONPs) as a glioblastoma-targeting theranostic agent. As shown in Fig. 12a–d, a T2-weighted MRI signal drop was observed at the U87ΔEGFRvIII glioma tumor region after CED of EGFRvIIIAb-IONPs, and the darkened area was wider 7 days after CED, indicating that nanoparticles had dispersed. The survival curves of animals that underwent CED with EGFRvIIIAb or EGFRvIIIAbIONPs revealed a substantial antitumor effect as a result of EGFRvIIIAb-mediated inhibition of EGFR phosphorylation, whereas CED with IONPs did not cause an enhancement in survival rate compared with untreated controls (Fig. 12e). Nanoparticles dispersed over time may also potentially target infiltrating brain tumor cells outside the tumor mass. Overall, these observations suggest that the targeted delivery of magnetic nanoparticles via CED may enable advancements in the treatment of malignant glioblastoma. Dendritic cell (DC)-based immunotherapy has been explored as a potentially potent therapeutic strategy against human cancers [87–89]. Nanoparticles are good candidates for delivering antigens into DCs owing to their large surface areas incorporating multiple therapeutic agents; however, their clinical application is limited by cytotoxicity [17, 90]. Cho et al. developed multifunctional core–shell nanoparticles consisting of an iron oxide (Fe3O4) core covered with a photonic zinc oxide (ZnO) shell for DC-based cancer immunotherapy [91]. In this study, therapeutic nanoplatforms were used not only to deliver the therapeutic antigens but also to monitor the migration of DCs into lymph nodes by in

vivo MRI. Uniformly spherical and monodispersed Fe3O4–ZnO core–shell nanoparticles were synthesized via a modified nanoemulsion method. For efficient antigen delivery, a triple tandem repeat of a ZnO-binding peptide (3× ZBP) was genetically fused to carcinoembryonic antigen (CEA), a tumor antigen, and then incubated with the core– shell nanoparticles. The intracellular uptake of CEA nanoparticles did not cause significant cellular toxicity. Nanoparticle-labeled DCs were injected into the hind footpads of C57BL/6 mice, and DC trafficking was monitored by in vivo MRI. As shown in Fig. 13a–c, hypointense regions reflecting the presence of nanoparticle-labeled DCs were identified within central parts of the draining lymph node, indicating that nanoparticle-labeled DCs that had migrated into the central T cell zone of draining lymph node were visible by MRI. In contrast, free nanoparticles were generally passively distributed to the subcapsular region of the lymph node due to lymphatic vessel-mediated transport. An increase in the number of IFN-γ-secreting CD8+ T cells was observed in spleens of mice immunized with nanoparticle-labeled DCs, but not in control groups (Fig. 13d, e), implying CEA-specific cellular immunity mediated by nanoparticlelabeled DCs. Figure 13f–h shows that immunization with nanoparticle-labeled DCs significantly enhanced tumor growth inhibition and survival of mice.

Fig. 12 a T2-weighted MRI showing a tumor xenograft with a bright signal 7 days after tumor implantation (arrow). b Tumor (arrow) shown by contrast enhancement after injection of gadolinium contrast agent (Gd-DTPA). c MRI signal drop (arrow) after CED of EGFRvIIIAb-IONPs. d EGFRvIIIAb-IONP dispersion and T2 signal

drop (arrow) on MRI 4 days after CED. e Comparison of survival curves after intracranial implantation of athymic nude mice with human U87ΔEGFRvIII cells and treatment with MRI-guided CED of HBSS (control), IONPs, EGFRvIIIAb, or EGFRvIIIAb-IONPs. Reproduced with permission from [83]

Conclusions and future perspectives MRI-guided drug delivery allows for the noninvasive detection of disease sites, assessment of drug accumulation in target tissues, and prediction of treatment responses in

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Fig. 13 a In vivo MR images of draining lymph nodes of a mouse injected in the ipsilateral footpads with DCs labeled with Fe3O4–ZnO (red arrow) or ZnO nanoparticles (yellow arrow). b Draining lymph node (green arrow) of a mouse injected with cell-free Fe3O4–ZnO nanoparticles. c Representative immunohistochemistry of a draining lymph node after injection with Fe3O4–ZnO nanoparticle-labeled DCs (dark brown dots). T T cell zone, B B cell follicle. d, e CEA-specific, IFN-γ+ CD8+ T cell responses of mice immunized with DCs. d Representative dot plots. e Average percentages of cytotoxic T lymphocytes from three independent experiments. f, g Tumor volumes and

survival rates of mice injected with MC38/CEA cells. Mice were immunized with DCs loaded with nanoparticle/3× ZBP-CEA (open red squares), nanoparticle/CEA (filled red squares), 3× ZBP-CEA (open blue triangles), CEA (filled blue triangles), nanoparticles only (open black circles), or DCs only (filled black circles), four times at weekly intervals starting 1 week after tumor injection. h Tumor growth in human CEA transgenic mice inoculated with MC38/CEA cells. Mice were immunized with DCs three times at weekly intervals. Reproduced with permission from [91]

real time. To achieve this strategy, researchers have focused tremendous effort on the development of magnetic nanoparticle-based theranostic platforms. Owing to their intrinsic magnetic properties, magnetic nanoparticles lend themselves to diagnostic MRI applications. Notably, this property also enables hyperthermia therapy and local drug delivery under an external magnetic field. Additionally, because their surfaces are easily fabricated to contain a variety of targeting moieties, such as antibodies, peptides, aptamers, or therapeutic agents, multifunctional magnetic nanoparticle systems can be used for simultaneous disease

diagnosis at an early stage and systemic delivery of therapeutic agents to target sites. A number of such applications have been reported in recent years. This approach seeks to optimize the properties of drug delivery systems and understand important aspects of the responses to the therapy around pathological sites, with the ultimate objective of developing optimal treatment schedules for individual patients. Thus, MRI-guided drug delivery can offer real-time feedback to the practitioner and improve the balance between efficacy and toxicity of targeted interventions.

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Theranostic nanoplatforms and image-guided drug delivery will be used for various objectives, ranging from simple assessment of drug distribution to complex adjustments to achieve a successful treatment regime, but all share the same goal of facilitating personalized medicine. The development of new theranostic nanoplatform design principles and implementation strategies will contribute to translating these therapeutic systems into clinical practice. Acknowledgments This work was supported by Korea Ministry of Knowledge Economy under KORUS Tech Program (KT-2008NTAPFS0-0001).

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Magnetic nanoparticles and their applications in image-guided drug delivery.

Magnetic iron oxide nanoparticles have been shown to be suitable for use as theranostic agents owing to their intrinsic diagnostic capabilities in mag...
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