A review of magnet systems for targeted drug delivery

Journal of Controlled Release 302 (2019) 90–104

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Review article

A review of magnet systems for targeted drug delivery Ya-Li Liu

a,b

a

, Da Chen , Peng Shang

a,b

, Da-Chuan Yin

a,b,⁎

T

a

Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, PR China Shenzhen Research Institute of Northwestern Polytechnical University, Shenzhen 518057, Guangzhou, PR China

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A R T I C LE I N FO

A B S T R A C T

Keywords: Drug delivery Magnetic drug targeting Magnet systems Magnetic drug carrier Magnetic nanoparticles Drug delivery system (DDS)

Magnetic drug targeting is a method by which magnetic drug carriers in the body are manipulated by external magnetic fields to reach the target area. This method is potentially promising in applications for treatment of diseases like cancers, nervous system diseases, sudden sensorineural hearing loss, and so on, due to the advantages in that it can improve efficacy, reduce drug dosage and side effects. Therefore, it has received extensive attention in recent years. Successful magnetic drug targeting requires a good magnet system to guide the drug carriers to the target site. Up to date there have been many efforts to design the magnet systems for targeted drug delivery. However, there are few comprehensive reviews on these systems. Here we review the progresses made in this field. We summarized the systems already developed or proposed, and categorized them into two groups: static field magnet systems and varying field magnet systems. Based on the requirements for more powerful targeting performance, the prospects and the future research directions in this field are anticipated.

1. Introduction With the advancement of medical sciences, more and more drugs have been successfully developed and utilized to cure human diseases. In the traditional way of disease treatments, the drugs are usually taken orally or injected, so that the drugs will be distributed to a large extent throughout the whole human body. Such situation will cause damages to the body's normal cells and tissues, resulting in side effects that are always unwanted, and even bring serious problems to the patients. Targeted drug delivery is a good solution to this problem in that it can not only cure the disease efficiently, but also reduce the dosage and the side effects. This is particularly important for the treatment of diseases like cancers, nervous system diseases, sudden sensorineural hearing loss, and so on [1–5]. Drug targeting aims to deliver drugs to the lesion site, which can improve the efficacy, reduce the dose of drugs and the side effects. Currently, there have been many ways studied or proposed to achieve drug targeting [6–9], including utilization of physical environments like light, electricity, ultrasonic, and magnetic field. Among these physical environments, magnetic field is an attractive means, which is called magnetic drug targeting. Magnetic drug targeting is a method by which magnetic drug carriers in the body are manipulated by external magnetic fields to reach the targeted area. Magnetic drug

carriers contain magnetic materials that interact with magnetic fields, usually magnetic nanoparticles such as ferric oxide particles. Compared with other ways of drug targeting, magnetic fields can pass through the body safely, so magnetic carriers can, in principle, be directed to deep tissue targets. In the 1950s, magnetic fields were first used for drug targeting [10,11]. In 1957, Gilchrist et al. [10] proposed using a magnetic field to realize thermal effects in the body. In 1963, Meyers et al. [12] introduced a method of using a horseshoe magnet placed outside the body to accumulate small iron particles in the body. After that, magnetic drug targeting has aroused widespread concern and rapid development [13,14]. Magnetic drug targeting was first applied in clinical trials in 1996 [15], where a single permanent magnet with a magnetic flux density of 0.8 T was placed near the surface of the skin to treat the tumor. There have been a lot of researches on magnetic drug targeting over the past decades, which can be mainly summarized into two parts. The first part is the research on the preparation of magnetic carriers (also known as DDS [16,17]), which is the most studied theme in magnetic drug targeting. The DDS should be different for different disease types and targeted sites, and it must be biocompatible, nonimmunogenic and non-toxic [18,19]. Such research involves the selection and modification of the material of the carriers, the manner in which the drug is combined with the carriers, and the like. The second

⁎ Corresponding author at: Institute for Special Environmental Biophysics, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, PR China. E-mail address: [email protected] (D.-C. Yin).

https://doi.org/10.1016/j.jconrel.2019.03.031 Received 12 March 2019; Received in revised form 28 March 2019; Accepted 29 March 2019 Available online 01 April 2019 0168-3659/ © 2019 Elsevier B.V. All rights reserved.

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(polyvinyl alcohol coated magnetic carrier nanoparticles), Kayal et al. [40] found that cylindrical magnets are more suitable for the purpose than rectangular ones.

part is the magnet design. In magnetic drug targeting, the magnetic field determines the direction of movement of the drug in the body. An ideal magnetic field shall be able to drive the magnetic carriers in the body to reach any position in the body. As a tool for manipulating magnetic carriers, magnets play an important role in magnetic drug targeting. Developing or choosing ideal magnet systems for specific targeting purposes is thus very important. Therefore, it is necessary to review the existing magnet systems or designs for drug targeting magnet. Up to now, most of the existing review articles on magnetic drug targeting focus on magnetic carriers [9,20–24]. Although there are already articles [21,25,26] reviewing the magnet designs for drug targeting, they mainly focused on designs of magnet for manipulating medical device [26], or more on magnetic targeting principles [25]. The latest progresses and a comprehensive overview on the magnet systems or the designs are necessary. In this paper, the magnet systems used for magnetic drug targeting are summarized into two categories: static field magnet systems and varying field magnet systems. Finally, the prospect of magnetic drug targeting magnet and the future research direction is discussed.

2.1.2. Permanent magnet assembly The single permanent magnet is convenient to be used. However, in the process of drug targeting, a specially designed magnetic field distribution with higher magnetic field and more specific field distribution may be better suited for the targeting purpose. For example, at present, the maximum remanence of a single permanent magnet can reach about 1.5 T. To achieve higher field intensity, utilization of more than one permanent magnet is necessary. Permanent magnet assembly is a unit comprises of two or more permanent magnets, assembled into an integrated magnet system specially designed for achieving required magnetic field distribution. Among many different designs of magnet assembly, the best way of increasing the magnetic field is the Halbach array. Halbach array was first proposed by American physicist Klaus Halbach in 1979 [41]. The main principle of the Halbach array to increase the magnetic field is to “squeeze” the magnetic field in one direction by having a spatially rotating pattern of magnetization. In this way, the magnetic field on one side of the array increases and the magnetic field on the other side weakens. With the use of Halbach array, the magnetic field induced by permanent magnet can reach up to 4–5 T [42,43]. Apparently, the Halbach array can be applied to magnetic drug targeting, with enhanced targeting performance due to more suitable field strength and field distribution. Most of the magnet systems are constructed layer by layer. According to the number of magnet layers in the structure, we classified the magnet assembly into two groups: single-layered magnet array, and multiple-layered magnet array.

2. Static field magnet systems Static field magnet systems are the ones in which the magnetic field remains constant over time. According to the source from what the field is generated, the systems can be divided into two categories: permanent magnet system and electromagnet system. 2.1. Permanent magnet(s) 2.1.1. Single permanent magnet Single permanent magnet is the simplest magnet for magnetic drug targeting. The methods for magnetic drug targeting using single permanent magnet are shown in Fig. 1. Fig. 1A is used in animal and clinical trials where the magnet can be placed anywhere on the surface of the body near the lesion site. Due to the attractive force caused by the permanent magnet, the DDS carrying the drugs will be captured to the region near to the magnet. Fig. 1B is used for simulation experiments. The sample container can be a container containing magnetic nanoparticles [27–31], a cell culture dish for studying the effect of cell capture on nanoparticles [32,33], an artificial pipe (including straight [34,35], Y-shaped [36,37], multi-branched structures [38]) for the simulation of blood vessel, and so on. The magnet used may be a permanent magnet of different shapes and sizes. The targeting performance is closely related with the shape and size of the magnet. Compared with electromagnets, permanent magnets have more diverse shapes. The shape of permanent magnets for practical applications is an important issue to be considered. Depalo et al. [39] compared the uptake of nanoparticles by cells in the field of two different permanent magnets (ring- and square-shaped) placed under the cell culture dish. Both magnets have the same magnetic induction (B = 1.17 T). The results showed that the ring magnet seems to be more effective. In a simulation experiment on deposition of magnetic nanoparticles

2.1.2.1. Single-layered magnet array. Fig. 2 gives examples of some single-layered magnet arrays. Fig. 2A [44] shows a structure of single-

Fig. 1. Schematic illustration of magnetic targeting using single permanent magnet. A. Attach the magnet to the skin near the lesion site, so as to attract the DDS to the site near the magnet. B. Place the magnet near to the sample container, so that the DDS can be pulled to the site near the magnet.

Fig. 2. Examples of the structures of single-layered magnet assemblies. A (side view), B- D (top view) [44] are different designs for making magnetic bandages. E (side view) [45,46] is a design for pushing instead of trapping magnetic particles. 91

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layered Halbach array. The linear Halbach array (Fig. 2A) was designed to increase the field in one side (lower side) and decrease in the other side (upper side), which would be useful as a magnetic bandage. Figs. 2B-2D show three other magnet arrays designed for magnetic bandages [44], which are also single-layered arrays. The structures of the arrays are similar to each other. The only difference is that the magnetization directions are different. These designs were compared with the linear Halbach array, and it was found that the Halbach array shows better particle trapping capability [44]. Fig. 2E shows a unique design of magnet pair. Normally the magnet attracts magnetic nanoparticles, while Shapiro et al. [45,46] desgined a two magnet system which created a localized low field in front of the magnet by placing the two magnets at an angle (Fig. 2E). The magnetic particles placed in that area will be pushed away (instead of being attracted). This system may be used to treat diseases of the inner ear and eyes. In addition to the above arrays, other types of designs are also possible. For example, Al Faraj et al. [47] compared the effects of bipoles and multi-poles permanent magnets on magnetic drug targeting. They taped these two magnet systems to the shaved chest of mice for targeting superparamagneitc iron oxide nanoparticles (SPION). The research results showed that the permanent magnet structure with multi-poles enhances the particle targeting effect compared to the case of non-magnet and the case with bi-poles magnet structure. Babincova et al. [48] designed an annular array of permanent magnets consisting of eight sphenoid block permanent magnets of the same shape and size, and the magnetization directions of the adjacent two permanent magnets are 135 degrees. They simulated the capture process of this array for 10 μm and 50 nm magnetic particles, and the results showed that larger particles are easier to be captured.

Fig. 4. Examples of complex 3-D Halbach arrays used in magnetic drug targeting [54,56]. The direction of the arrows is the magnetization direction of the magnet. A. A multiple layered linear Halbach array. B. A 3-D spatial Halbach array.

magnet structure can target cells to the posterior tibial artery with a targeting efficiency up to 6.25%. In addition, Shen et al. [53] compared the retention effect of this structure with two different sizes of cylindrical permanent magnets on super-paramagnetic iron oxide nanoparticles in deep brain regions, the results showed that the Halbach array was more effective. More complicatedly, complex three-dimensional (3-D) arrays could be spliced using multiple small magnets with different magnetization directions, including a multi-layer space structure composed of different linear arrays [54] and a 3-D structure composed of block magnets of different magnetization directions [55–57]. Fig. 4 illustrates some examples. Fig. 4A is a multiple layered linear Halbach array designed by Hayden et al. [54], each of which has a different magnet shape and magnetization direction. Fig. 4B is a spatial array designed by Barnsley et al. [56], which consists of six different magnetization directions. As shown in the Fig. 4, different colors represent different magnetization directions, and magnets with the same magnetization direction are formed by splicing a plurality of small magnets.

2.1.2.2. Multiple-layered magnet array. Multiple-layered magnet array utilized more than one layer of magnet array, and it may create even stronger field and better field distribution for specific drug targeting purpose. Fig. 3A shows an annular Halbach array, which was optimized by Munoz et al. [49,50] through theoretical calculation, software analysis and other methods. For that structure, two layers of identical 12 arcshaped permanent magnets were used to form a hollow cylindrical (inner diameter 60 mm, outer diameter 100 mm, thickness 60 mm) array, which was design for drug targeting of capsule robots [51]. Riegler et al. [52] conducted a relatively comprehensive study of magnet designs used for drug targeting. They compared the magnetic forces caused by four kinds of magnets (annular Halbach array, linear Halbach array, triangular rod and magnetic bar). The effects of different magnetization arrays, magnet radii, magnet thickness, etc. were also compared. The results showed that the best magnet design for the calf artery experiment was an annular Halbach array of 12 permanent magnets. The magnetization directions of two adjacent magnets in the array are at a 90 degrees angle. Four permanent magnets magnetized along the axial direction of the array are installed at both ends of the array, as shown in Fig. 3B. Numerical simulations predict that this

2.2. Static field electromagnet(s) Electromagnets are another choice to create magnetic field of desired field strength and distribution. The design of the static electromagnet includes the considerations of factors on shape, size, current or voltage. Hajiaghajani et al. [58] studied the effects of different electromagnet parameters on magnetic drug targeting. It includes the height, inner diameter, outer diameter and wire diameter of the coil, the voltage of the coil, and the distance from the coil to the container. Pondman et al. [59] designed an U-shaped electromagnet. The two poles of the electromagnet are different in size in order to obtain higher gradient value, and the spacing between the two poles was designed to be 3 cm for the rat thigh experiment. In order to guide the Magnetic Nanoparticles (MNPs) through the blood-brain barrier, Hoke et al. [60] used Comsol to design and optimize a structure capable of generating high gradient magnetic fields. As shown in Fig. 5A, the design includes an electromagnet and a C-shaped iron yoke. The electromagnet has a magnetic core. In order to obtain a higher gradient magnetic field, one side of the core adopts a tip design, and the specific size of the tip is optimized using Comsol. In a permanent magnet or electromagnet, the magnetic field always has its highest magnetic field at the corner. In a tip-top design, the magnetic field of the tip will be relatively high and the magnetic field gradient around the tip will be relatively high. Therefore, higher forces can be generated on the nanoparticles, guiding them through the blood-brain barrier. Actually, tip-top design is used by many researchers as a good design to increase magnetic field strength and gradient. For example, in a high gradient magnetic field designed by Alexiou [61], the design of magnet structure (as shown in Fig. 5B) also used the tip-top design. In addition, Voronin et al. [62] also used tip-top design. In an in vitro study of magnetic field capture of microcapsules, they placed a

Fig. 3. Examples of annular Halbach array used in magnetic drug targeting [50,52]. The direction of the arrow is the magnetization direction of the magnet. 92

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Fig. 6. Schematic illustration of the process of a cross-shaped combined magnet system gradually guiding the intravascular DDS to the targeted site [68].

of nanoparticles by cells and facilitate the passage of nanoparticles through the barriers like blood-brain barrier. During the flow of blood, the flow velocity at the center of the blood flow and at the edge of the blood flow is different. Skiedraite et al. [68] established a magnet model containing two high magnetic field gradient zones for particle guidance in different blood flow velocities. The model consists of two linear Halbach arrays. As shown in Fig. 6, two arrays (one of which is shown in green and the other in purple) form a cruciform structure. The first high gradient region directs the particles from the center of the container to the edge. Then a portion of the array is removed, and finally the second high gradient region directs the particles to the targeted site. Karpov et al. [69] designed two permanent magnet rotation systems. One of the rotating systems contains twelve permanent magnets that are magnetized in the same direction and arranged in a checkerboard pattern. Two petri dishes were placed above each magnet and the magnets were moved under the petri dish in the manner shown in Fig. 7A. The direction of movement changed at a certain frequency. The rotating system can reduce the formation of nanoparticle chains under a magnetic field, thereby facilitating the interaction between the nanoparticles and the cells, and enhancing the uptake of the nanoparticles by the cells. The other rotating system consists of two permanent magnets, each moving along its own circular trajectory and appearing alternately below the culture dish, as shown in Fig. 7B. Using this rotating system, the nanoparticles placed in the petri dish on the two rotating magnets will aggregate into a “worm”-like line in the middle of the dish. The system enables particles to be concentrated in specific areas for targeting purposes. Krzyminiewski et al. [70] constructed a magnetic particle control system by rotating four permanent magnets. The system comprises two pairs of permanent magnets, each pair of magnets comprising a larger cylindrical magnet and a smaller cylindrical magnet. The two magnets are mounted opposite each other with a small intermediate distance, more installation details are shown in Fig. 7C. A container containing magnetic particle solution is placed between the two pairs of magnets. When the two pairs of magnets rotate about the axis between them, the magnetic particles would be concentrated in the middle of the container. Baun et al. [71] used three annular Halbach arrays to achieve two dimensional (2-D) manipulation of MNPs. One of the arrays produces a homogeneous magnetic field that is used to magnetize the particles and orient the particles. Another array produces a gradient magnetic field that exerts a force on the particles, and the direction of the force can be determined by changing the angle between the two arrays. To adjust the magnitude of the force, another gradient magnetic field is generated through the third array, and the intensity of the force can be adjusted by adjusting the angle between the two gradient magnetic field arrays.

Fig. 5. Examples of tip-top magnet system design [60–63]. A-D: the illustrations of the different magnet designs.

permanent magnet outside the glass capillary in the manner shown in Fig. 1B. The permanent magnet used adds a steel plate with a tip at one end to concentrate the magnetic field. In an in vivo study of magnetic drug targeting, they used two electromagnets, both of which had a sharp steel core at one end, with the two tips facing each other to create a magnetic field between them. The other side of the steel core is connected by a steel chain as shown in Fig. 5C. One of the electromagnets can be rotated to adjust the distance between the two tips. Agiotis et al. [63] used two face-to-face permanent magnets with the same magnetization direction to create a uniform magnetic field to magnetize the MNPs. An electromagnet is mounted next to the permanent magnet to create a gradient magnetic field for particle orientation. A magnetic core with a tip end (as shown in Fig. 5D) is also used in the electromagnet to enhance the magnetic field gradient. 3. Varying field magnet systems Varying field magnet systems refer to the ones in which the magnetic field changes with time. Such varying field magnet systems can be realized by the relative movement between the sample and the magnet. According to the source of magnetic field, the systems can be divided into two categories: moving permanent magnet system and varying field electromagnet system. 3.1. Moving permanent magnet(s) To obtain a changing magnetic field from permanent magnets, the magnets must constantly move around the sample. In other words, a mechanical system is necessary to realize the movement of the magnets [64,65]. Usually, the movement includes translational, rotational movements, and combined movements. Engelhard et al. [66] used a permanent magnet that rotates and translates simultaneously to direct the linear motion of magnetic particles. The permanent magnet was placed underneath a tray, and the movement of the particles in the tray is guided by the rotational and translational movement of the magnet. The device they built was used to test the movement of magnetic particles. Mahoney et al. [65] used a permanent magnet that can rotate or translate with any axis in space to control the movement of a micro-robot in a pipeline. Min et al. [67] used the appearance and removal of a permanent magnet to establish a pulsed magnetic field. MNPs in the static magnetic field will have a certain degree of aggregation, the existence of aggregates is not conducive to the transport of particles, while the pulse magnetic field can reduce the formation of MNPs aggregates, so as to enhance the uptake 93

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Fig. 7. Examples of mechanical movements of magnets for drug targeting [69,70]. The direction of the arrow is the magnetization direction of the magnet.

existing MRI systems. One method is to add additional coils to the MRI system [90–93]. For example, Mathieu et al. [92,93] placed a set of Maxwell coil in the middle of the MRI system chamber to manipulate the iron oxide particles. The second method is the Dipole Field Navigation, which places several ferromagnetic cores on the surface of the body to distort the magnetic field and produce a high gradient magnetic field. Several studies have been carried out to design the size and position of the ferromagnetic cores [94–96]. In addition to the MRI system, there are also a small number of other superconducting coil designs, for example: Mcneil et al. [97] used six superconducting coils to construct a helmet in a roughly cubic array for manipulating magnetic material in the brain. The specific arrangement of the coil is shown in Fig. 8A. The coil in the Z-axis direction is horizontally placed, and the coils in the X-axis and Y-axis directions have a 45-degree angle and a negative 45-degree angle to the horizontal direction respectively. Mishima et al. [72] envisioned rotating a hightemperature superconducting bulk magnet around the capillary (shown in Fig. 8B), when a solution suspended with ferromagnetic particles passes through the capillary tube, the simulation results show that the ferromagnetic particles will gather in the middle of the capillary. Since it is difficult to rotate the superconducting magnet, in practice, the author chose to fix the superconducting magnet and the capillary rotates on the magnet. Experimental results verified the simulation results.

The design has a good theoretical basis, but due to the complexity of the structure, there are certain difficulties in actual machining. Therefore, the actual model of machining only contains one homogeneous magnetic field and one gradient magnetic field, which means that it can only adjust the direction of the force and cannot adjust the magnitude of the force. Baun et al. [71] achieved 2-D directional control of 30 μm MNPs by adjusting the angle between the homogeneous magnetic field and the gradient magnetic field array. This design can also extend from 2-D to 3-D particle manipulation from a theoretical perspective, but the required structure will be more complex and difficult to implement. 3.2. Varying field electromagnet(s) Realization of varying magnetic field can be achieved through mechanical movement and control of current. In practical applications, the mechanical movement of large electromagnets is usually inconvenient, so the movement of the sample is used to replace the mechanical movement of the large electromagnet, so that the magnet generates relative motion [72,73]. But in most cases people prefer to change electric current to achieve variable field, supplemented by mechanical movement when appropriate. There have been many studied or proposed electromagnet systems for magnetic drug targeting. According to the types of coils used to build the magnets, we classified the magnet systems into two categories: one is based on superconducting coils, which is mainly used in magnetic resonance imaging (MRI) equipments. The other is based on traditional coils, which can be further divided into three subclasses, which are based on ordinary coils, Helmholtz coils and/or Maxwell coils, and a combination of different types of electromagnets.

3.2.2. Magnet systems based on conventional coils 3.2.2.1. Magnet systems based on ordinary coils. This type of magnet systems are those based on the simplest electromagnet, which is built by using ordinary coils. The magnet systems can be simply an electromagnet with a single coil, or a mixture of two or more electromagnets. Yoon's group used two electromagnets to create functionalized magnetic fields of different waveforms [98–101]. The two magnets are placed face to face, each containing a magnetic core. Different types of magnetic fields are generated by changing the current in the two coils. The steering of nanoparticles under magnetic field and the effect of square wave electromagnetic fields with different frequencies on the guiding efficiency of nanoparticles were studied. Since the functionalized magnetic field can help nanopartices passing through the bloodbrain barrier, it was proposed to treat Alzheimer's disease.

3.2.1. Magnet systems based on superconducting coils This type of magnet system mostly uses MRI facilities, which are usually built using superconducting coil, supplemented by conventional coils, permanent magnets and/or other auxiliary devices to help achieve drug delivery. The magnetic resonance imaging (MRI) system contains a gradient magnetic field that can be used to manipulate magnetic particles in the body [74–80]. Drug targeting with MRI systems has its specific advantages. First, the MRI system can image specific areas, so the position of the particles in the body and the distribution of the blood vessels in the body can be observed by imaging. Secondly, the MRI system can calculate and correct the motion and adjust the generation of the magnetic gradient through feedback control algorithms, so as to navigate the magnetic particles in the pre-planned path and realize the stepwise guidance of the particles. However, due to the Joule effect, the gradient coil generates heat, so the gradient strength in clinical magnetic resonance is limited in order to prevent overheating. Studies have shown that magnetic fields generated by MRI systems can be used to drive ferromagnetic materials in the micron to millimeter range [76,81,82], or microdevices [83–88], as well as to guide the movement of magnetically labeled cells [89]. However, for the smaller-sized particles, such as the most commonly used magnetic nanoparticles in magnetic drug targeting, the magnetic field gradients in medical MRI systems are not satisfactory, so improvements are needed to do on

Fig. 8. Examples of superconducting coil design for magnetic drug targeting [72,97]. 94

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distribution of four magnets in different states, and controlled the morphology and direction of the movement of magnetotactic bacteria by adjusting the switch states and current direction and size of the coils. Khelil et al. [108–112] used four electromagnets arranged in the same way to control the movement of magnetic particles and micro-robots, and designed different current control methods. Zhang et al. [113,114] created an artificial bacterial flagella (ABF) control system using three sets of coils placed in the X, Y, and Z directions. Each set of coils contains two coils symmetrically centered around the origin of the coordinates, and a rotating magnetic field is generated by controlling the current in the six coils. The spiral ABF rotates with the rotation of the magnetic field and converts the rotational motion into a linear motion. The direction of the rotating magnetic field determines the forward or backward motion of ABF, while the control of the current in the coils on the three axes can adjust the direction of ABF motion. De Lanauze et al. [115] also created a control system using three pairs of orthogonally arranged coils. By designing the current ratio variations between different coils, different magnetic field sequences were constructed, and the 3-D motion of magnetotactic bacteria in solution was successfully achieved [116]. The same arrangement was also used by Pawashe et al. [117] to control the movement of micro-robots. More electromagnets were used in the design of Kummer et al. [118]. They used a total of eight coils (called OctoMag, as shown in Fig. 10A) to control the micro-robot in the body, and can control the micro-robot with five degrees of freedom (three position degrees of freedom, two direction degrees of freedom) wireless control. The OctoMag can also be used for the wireless control of in vitro venous puncture of vasculature of the chorioallantoic membrane. They also produced a miniature eight-coil device (MiniMag) with a similar structure, realized the 3-D motion control of the micro-robot [119]. Diller et al. [120] designed a micro-robot control system consisting of another eight electromagnet structure (shown in Fig. 10B), and combined with the design of micro robots, introduced a method to

Petruska et al. [102] designed an omnidirectional electromagnet (omnimagnet) consisting of three orthogonal nested solenoids and a spherical core wrapped in them. The three solenoids generate magnetic fields in three different directions in three dimensions. By controlling the current in the three solenoids, the desired magnetic field in space can be generated. Same as the permanent magnet described in the previous section that can move mechanically in space [65], the omnimagnet can also create a rotating dipole field. But the omnimagnet does not require complex mechanical motion, and it can also control the field strength by controlling the magnitude of the current. By using different magnetic control methods, the omnimagnet can be used to control the micro-robot move along different shapes of motion paths [103], such as squares, rose curves, and labyrinth. Tehrani et al. [104] proposed an electromagnetic system for manipulating nanoparticles. The system consists of six independent circular coils that are symmetrically arranged along three axes of the Cartesian coordinate system. Each coil has a magnetic core to enhance the magnetic field strength. The authors use finite element software to simulate and optimize the shape and size of coils and cores. By conveying the current only to part of the coils, the nanoparticles can be directed to the desired exit. Nacev et al. [105] created a micro-nano-scale ferromagnetic rods focusing system with four electromagnets. The four electromagnets are symmetrically placed in a 2-D plane. The ferromagnetic rods can be gathered in the positive middle of the 2-D plane by dynamic magnetic inversion control of the magnets. The aggregation processes of the ferromagnetic rod is shown in Fig. 9. Probst et al. [106] placed four magnets symmetrically along the Xaxis and Y-axis. The sample is placed between these four magnets. By controlling the switching state of the four coils, adjusting the current size and direction, the movement of ferromagnetic fluid drops in arbitrary shape paths (such as straight lines, squares, spirals, etc.) is realized. Loghin et al. [107] used similar methods to control the swarn formation of magnetotactic bacteria. They simulated the magnetic field

Fig. 9. Ferromagnetic rods aggregation processes. A: Energize two horizontal coils, the ferromagnetic rods aligned in the direction of the magnetic field; B: Turn off the current in the right coil, and the ferromagnetic rods repels to the right; C: Turn off the current in the horizontal coil, Energize two vertical coils, the ferromagnetic rods rotated to match the vertical field; D: Turn off the current in the upper coil, and the ferromagnetic rods repelled upwards; E: Turn off the current in the vertical coil, energize two horizontal coils and the magnetic field is opposite to the field in step A, the ferromagnetic rods rotated to match the horizontal field; F: Turn off the current in the left coil, and the ferromagnetic rods repels to the left; G: Turn off the current in the horizontal coil, energize two vertical coils and the magnetic field is opposite to the field in step C, the ferromagnetic rods rotated to match the vertical field; H: Turn off the current in the lower coil, and the ferromagnetic rods repelled downward. Repeat these eight steps again and again until the ferromagnetic rods gathered in the middle of the plane. [105]. 95

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Fig. 10. Examples of ordinary coil design for magnetic drug targeting [118,120,121].

axis direction are set to work alternately with a certain time function, the simulation results show that the particles can be targeted to the tumor site of the 3-D real vascular model.

independently control the motion paths of multiple micro robots in 3-D. Based on Diller ‘s design, Nam et al. [121] added a core to each coil and connected the eight magnets with two cross-shaped back-yokes to form a closed magnetic circuit (shown in Fig. 10C). The core and yoke can effectively increase the strength of the magnetic field. In addition, Nakamura and other people's design [122] also used eight electromagnets, but also the use of permanent magnets, as well as the rotation of the electromagnet. The designed control system is shown in Fig. 11, which includes a U-shaped yoke, eight electromagnets (Four magnets can adjust the Angle and are mounted on the upper end of the U-shaped yoke while the other four are fixed on the lower end of the Ushaped yoke), two pole pieces (Connect the four electromagnets at the upper and lower ends respectively) and two permanent magnets (embedded in the magnetic yoke). By adjusting the angle of the upper electromagnet, the sum of the current in the electromagnets and the ratio of the current between the various electromagnets, the path control of the micro-robot can be realized in 3-D space. Le et al. [123] used four pairs of actuation coil (ACC) arranged symmetrically within the XY plane. Each pair of ACC contains two coaxial coils with opposite current directions, resulting in a local low field at the top of the ACC. Two sets of ACCs placed opposite to each other along the X-axis will produce two local low fields between the two sets of coils. The middle region of the two local low fields is the focusing region of the particle in the X-axis direction, but in the static magnetic field the particle will move in the Y-axis direction. If two sets of driving coils are symmetrically placed in the Y-axis direction at the same time, the generated magnetic field causes the particles to move diagonally, and the particles cannot be focused in the middle of the four sets of coils. However, if the coils in the X-axis direction and the coils in the Y-

3.2.2.2. Magnet systems based on Helmholtz/Maxwell coils. This type of systems utilizes one or two of the classical coils, namely, the Helmholtz coil and the Maxwell coil. Both kinds of coils contain a set of coils placed face to face, but the parameters of the coils and the type of magnetic field produced are different. The distance between the two coils in a Helmholtz coil is equal to the radius of the coils, and the current in the two coils is in the same direction. Helmholtz coil can produce a homogeneous magnetic field. The distance between the two coils in a Maxwell coil is 3 times the radius of the coils, and the current in the two coils is in the opposite direction. The set of coils can generate a gradient magnetic field. These two classical coils are widely used in magnetic field designs because they can produce uniform homogeneous magnetic field and uniform gradient magnetic field in a large range of space. For example, Berk Yesin et al. [124] established a micro-robot steering control system. The system includes a Helmholtz coil and a Maxwell coil. The two sets of coils are arranged adjacent to each other in the axial direction and can be rotated around the coordinate system Y axis (as shown in Fig. 12A). A flat platform is fixed between the coils, where the micro-robot is placed. The movement direction of the micro-robot in the horizontal plane can be controlled by the rotation of the coils and the adjustment of the current in the coils. Another micro-robot steering control system proposed by Choi et al. [125] also uses Helmholtz coils and Maxwell coils (Fig. 12B). The difference is that they are designed using four sets of fixed coils. Two Helmholtz coils are placed perpendicular to each other in a plane. By adjusting the current ratio between the two Helmholtz coils, a uniform magnetic field in different directions can be generated for orienting the micro-robot. Two Maxwell coils are also placed perpendicular to each other in this plane, and the Maxwell coils are mounted on the outside of the Helmholtz coils (as shown in the Fig. 12B). By applying different current ratios between the two Maxwell coils, the direction of motion of the micro-robot can be adjusted. By rotating one of the Helmholtz-Maxwell coils in another plane, the system has been extended to the 3-D motion control of the micro-robot [126]. The rotation method is: The two sets of coils in the X-axis direction are fixed, and the two sets of coils in the Y-axis direction are rotated around the X-axis. Using this system, Jeong et al. [126] successfully controlled the movement of a cylindrical permanent magnet with a diameter and thickness of 1 mm in a 3-D vascular model. Kwon et al. [127] prepared a similar 3-D control system of Micro-robots based on the same principle. And successfully controlled the direction of motion of an 800-μm diameter spherical robot (cylindrical permanent magnet covered with clay) in a T-shaped tube. In addition, Ha et al. proposed using three sets of Helmholtz coils and one Maxwell coils to achieve 3-D control of the micro-robot, and designed circular coils (shown in Fig. 12C) [128] and square coils (shown in Fig. 12D) [129].

Fig. 11. Combination design of eight electromagnets and two permanent magnets [122]. 96

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a pair of uniform magnetic field saddle coils (as shown in Fig. 13B). By controlling the current in the four pairs of coils, the micro-robot can be oriented and driven to move. Using this system, the author successfully controlled the motion of a cylindrical permanent magnet (with a diameter and a height of 2 mm) at different angles in a plane [136]. By rotating two pairs of saddle coils, Choi et al. [137] realized the movement of a cylindrical permanent magnet (1 mm in diameter and 5 mm in height) in different directions in 3-D space. It is also realized to guide the magnet through different outlets in the 3-D vascular model. Lee et al. also used a similar coil structure design to construct a wireless capsule endoscope drive system. The system consists of five pairs of coils, including a pair of Helmholtz coil, a pair of Maxwell coil and three pairs of rotating saddle coils. The Helmholtz coil and the two pairs of rotating uniform magnetic field saddle coils can produce a uniform magnetic field in different directions to orient the capsule endoscope. The Maxwell coil and a pair of rotating gradient magnetic field saddle coils generate a gradient magnetic field to push the endoscope. The system can drive the translation, rotation, and spiral motion of the endoscope through the rotation and current control of the coils [138]. It can also be used to drive capsules containing soft magnets and control the release of drugs [139]. Subsequently, Nam et al. [140] used three uniform magnetic fields (one produced by a pair of Halmholtz coil and the others by two pairs of rotating saddle coils) to drive a specially designed magnetic helical robot and control drug release to the targeted location. Han et al. [141] designed a magnetic drug delivery system using three coils, including a Helmholtz coil and two racetrack coils (as shown in Fig. 13C), with the two racetrack coils placed perpendicular to each other. The Helmholtz coil produces a uniform magnetic field for rotating and orienting magnetic particles. The Helmholtz coil produces a linear gradient magnetic field with any of the racetrack coils. The Helmholtz coil together with the two racetrack coils produces a maximum gradient magnetic field at the intersection of the two racetrack coils, so it is expected to concentrate the particles above the intersection of the two racetrack coils. The design is still in the theoretical design phase and has not been experimentally verified.

Fig. 12. Examples of Helmholtz coil and Maxwell coil applications for magnetic drug targeting [124,125, 128, 129, 132–134].

However, the actual experiment only realizes the control of different paths of a cylindrical permanent magnet in a 2-D plane. Arcese et al. [130,131] proposed using one Helmholtz coil and three sets of maxwell coils to realize the 3-D control of the micro-robot. The instrument realized the navigation of a permanent magnet in a branched pipeline. The coils are arranged in a similar manner to Fig. 12C and Fig. 12D. Cheang et al. designed approximate Helmholtz coils in consideration of the size of the viewing system. Unlike the Helmholtz coil, the distance between the designed approximate Helmholtz coils is not equal to the radius of the coil, but equal to the outer diameter of the coil plus the thickness of the coil. The resulting magnetic field is less uniform than the magnetic field produced by the Helmholtz coil, but close to the homogeneous field. They have designed a robotic microswimmer control system consisting of two sets of approximate Helmholtz coils placed symmetrically in the X and Y directions (shown in Fig. 12E) [132,133], and a robotic microswimmer control system consisting of three sets of approximate Helmholtz coils symmetrically placed in X, Y, Z three directions (shown in Fig. 12F) [134].

4. Summary and future perspectives 4.1. Summary In magnetic drug targeting, the DDS carrying drugs reaches the lesion area under the guidance of an external magnetic field. As shown in Fig. 14, a complete magnetic drug targeting task mainly involves the DDS and the magnet systems. There are several types of DDSs used in magnetic drug targeting [142–144], including functionalized MNPs, capsules or microspheres containing magnetic particles, and cells injected with magnetic particles. Different DDSs are used according to different lesion sites and disease types. But all DDSs for magnetic drug targeting should contain magnetic particles that interact with the external magnetic field. As a tool to target the DDS to lesion site, the magnet system plays a crucial role in magnetic drug targeting. Different magnet systems will be used according to different DDSs and lesion sites. Table 1 summarizes the existing magnet designs for magnetic drug targeting and compares their advantages and disadvantages. From the table, it can be seen that, the static field magnet systems are simple and convenient to use, but its target accuracy is not very satisfactory. Varying field magnet systems have relatively high targeting accuracy and thus may be applicable for 3-D precise targeting, but they are inconvenient to use due to the complexity of the hardware systems. Compared with the fields created by electromagnets, those created by permanent magnets are relatively simple, convenient and energy saving. However, the magnetic field (B) and the magnetic field gradient (B′) of the latter are relatively low, while the former have relatively high magnetic field and field gradient, but more energy consuming.

3.2.2.3. Combined systems. The type of combined systems is more complicated as compared with the above two types. They can be combination of Helmholtz coil, Maxwell coil and ordinary coils. The design of Afshar et al. [135] includes three pairs of Helmholtz coils and three pairs of cylindrical electromagnets (as shown in Fig. 13A), combining the multi-input multi-output trajectory tracking controller (MIMO) as the electromagnetic navigation system. Jeon et al.'s design used a combination of Helmholtz coils, Maxwell coils, and ordinary coils. At the same time, in order to be applied to human clinical, the design of the coil shape is combined to give a comfortable lying space. The system consists of a pair of Helmholtz coil, a pair of Maxwell coil, a pair of gradient magnetic field saddle coils and 97

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Fig. 13. Examples of the combined design of Helmholtz coil, Maxwell coil and ordinary coil [135,136,141].

systems. These factors include: (1) Location of the lesion site. If the lesion site is on the body surface or near the skin, it will be easy to find a suitable magnet which can be placed on the surface of the body, so as to attract the MNPs to the lesion site. Or if the lesion site is close to the wall of tubes (such as intestinal tubes, blood vessles, etc.), one possible solution is to place the magnet or soft magnetic materials into the tubes to guide the MNPs to the lesion site; (2) Shape and size of the lesion. The magnetic field design shall meet the requirement of targeting the MNPs to suitable sized and shaped lesion. For instance, when the size of the lesion is large, the targeting magnetic force can be samller; (3) Number of the lesions. If there are two or more lesions in the body, one must consider the strategy to achieve the targeting: either simultaneous targeting, or sequential targeting. In the former case, one must design the magnet systems corresponding to multiple targets. Otherwise, one may have to do it sequentially so that the targets can be separately treated. 4.3. Research directions in developing advanced targeting systems Fig. 14. Schematic illustration of magnetic drug targeting.

In addition to the above mentioned existing or proposed magnet systems, which are necessary to be studied further, there are still many more possible systems that can be potentially useful in the future studies or applications. Furthermore, related studies, including the mechanism studies, and clinical application studies, are also necessary for future development of magnet systems. Fig. 15 shows schematically the research directions neccesary in developing advanced targeting systems in order to truly realize the wide application of magnetic drug targeting.

4.2. Factors to be considered for developing magnet systems The DDS in the body is transmitted to the lesion site through blood or body fluids. In this process, MNPs are those which interact with the magnetic field, the physical environment of the particles is complicated and the MNPs are subjected to a combination of forces such as magnetic dipole interaction, van der Waals force, thermodynamics, buoyancy, viscous resistance, and so on [48]. There are also many natural barriers including the blood-brain barrier, the gas-blood barrier, the bloodthymus barrier, and the like in the body. It is sometimes necessary to pass one or some of these barriers during drug targeting. If we want to use magnets to manipulate magnetic particles in the body, the magnetic force must be large enough to overcome these forces and obstacles. The force of the magnetic field on the magnetic particles can be expressed by the following formula [145]:

Fm = −V

χ BB′ μ0

4.3.1. Design of novel magnet systems 4.3.1.1. 3-D precise targeting magnet system. The ultimate goal of magnetic drug targeting is to achieve precise targeting anywhere deep in the body. However, this goal has not been perfectly achieved yet, due to the fact that the magnetic drug carriers and magnetic fields always attract each other, and magnetic drug carriers always move to the highest magnetic field position. In a static magnetic field, whether it is a permanent magnetic field or an electromagnetic field, the highest position of the magnetic field is in the magnet itself. Therefore, when a magnet is placed outside the body, the magnetic drug carrier in the body always tends to move toward the body surface, and thus it is difficult to achieve deep targeting. It is also the reason why magnetic drug targeting is currently mainly used in the surface targeting. Although it is difficult, researchers are still trying to achieve this goal. The possible solutions include: 1) Placing a ferromagnetic substance in the in vivo lesion area by means of minimally invasive surgery [146–148]. When an external magnetic field is present, the ferromagnetic material in the body is magnetized, creating a local high field in the lesion area; 2) With the help of micro-robots [77,149]. Micro-robots typically contain actuators so that an external magnetic field can deliver the drug to the lesion site with the assistance of an actuation system; 3) Realization of localized high magnetic field in 3-D free space by magnet design for 3-D precise targeting.

(1)

where Fm is the magnetic force, V is the volume of the magnetic particles, χ is the volume magnetic susceptibility of the magnetic particles, and μ0 is the magnetic permeability of the vacuum. B and B′ are the magnetic field and the magnetic field gradient of the magnet, respectively. According to the above formula, the factors to be considered in designing the magnet systems include: (1) the magnetic susceptibility (χ) of the MNPs. This factor is related with the type of materials, and its status that determine the magnetic susceptibility; (2) the size (V) of the MNPs. The larger the MNPs are, the easier to be affected by the magnetic field; (3) the field and field gradient product (BB'). First the field must be gradient, second, the field and field gradient must be large enough to obtain a larger magnetic force. In addition to the above factors, other factors related with the lesions are also necessary to be considered when developing the magnet 98

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targeting,

[98, 103–105, 111, 114, 117, 121, 122, 125, 126, 130, 134, 135, 138, 141] Exact calculation needed, energy consuming

targeting,

Fig. 15. Research directions neccessary in developing advanced targeting systems.

The first two methods combine techniques other than magnetic fields, and the magnetic fields used include simple magnetic fields and specially designed magnetic fields. The third solution is to create a localized high field. However, it is in principle impossible to achieve 3-D precision targeting using static magnetic fields. Therefore, the design of magnetic field for 3-D precision targeting is mainly the design of dynamic magnetic field, including the mechanical movement of the magnet and the change of electromagnetic current and frequency control. Although the mechanical movement of the magnet is one of the ways to achieve precise targeting, there are some drawbacks [121]: first, the magnetic field cannot be changed quickly because the magnet needs to be physically moved. Second, since this motion requires a lot of space, it is difficult to increase the number of magnets. Third, the field of permanent magnet cannot be “shut down” even in an emergency, so it may cause safety problems. Hence utilization of the change in the current and frequency is more practically feasible, which is the third solution to realize 3-D precise targeting. The third solution can avoid the drawbacks to some extent. It can change the magnetic field in real time by changing the current, and the types of magnetic field obtained is more than the types of magnetic field obtained by mechanically moving permanent magnets. On the other hand, there is no need for complex mechanical motions in this method, which saves a lot of space. At the same time, the electromagnet can stop the magnetic field at any time by turning off the current. However, the existing 3-D targeting magnet system are not ideal and have not been applied in clinical practice. The ideal 3-D targeting magnet system should have the advantages of precise targeting, simple structure, low cost, easy operation, easy promotion, and so on. Therefore, the development of 3-D precise targeting magnet system is still very important.

4.3.1.2. Other magnet systems. Besides the aforementioned 3-D precise targeting magnet systems, some systems with consideration of other techniques can be explored. For examples, attempts can be made to combine the magnetic targeting techniques with other targeting techniques, such as utilization of specific binding with the targets. Such combination may enhance the efficiency of the targeting. Other possible approaches can include utilization of biodegradable

Varying field magnet systems

Static field electromagnet(s) Moving permanent magnet(s)

Varying field electromagnet (s)

Magnet systems based on superconducting coils Magnet systems based on conventional coils

Simple, high B and Relatively accurate relatively simple Relatively accurate high B and B′ Relatively accurate high B and B′

B′ tarteting,

[58–63] [65–71]

[15,39,40] [44,47,51,52,54,56]

Inaccurate targeting, low B and B′ value Inaccurate targeting, complicated structure, difficulties in assembling Inaccurate targeting, energy consuming Inconvenient or necessary movement of magnet(s) Exact calculation needed Static field magnet systems

Permanent magnet(s)

Single permanent magnet Permanent magnet assembly

Simple, convenient, low cost Relatively high B and B′

References Disadvantages Advantages Category

Table 1 Comparison and summary of different magnet systems.

[72, 74, 76, 86, 92, 95]

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permanent magnet which is implantable in the body, or field-reactive soft magnetic/permanent objects that can be placed in the gut and blood vessels.

magnetic drug targeting, a suitable magnet system is a prerequisite. In this paper, we outlined various developed or proposed magnetic systems for magnetic drug delivery. At present, although there are many different types of magnet systems, their practical applications are often limited to some simple cases, such as diseases on the skin surface or close to the body surface. Therefore, the extent of promotion and application of targeted magnetic drug delivery is limited. For diseases deep in the body, although there have been studies on 3-D precise targeting magnet system, it is still in the fundamental research stage. Many models are preliminary and have not been fully tested. 3-D localized high magnetic field may be the best way to achieve precise targeting, but there is no real 3-D precise targeting yet. Therefore, we believe that, in order to truly realize the wide application of magnetic drug targeting, more fundamental researches are still necessary, including:

4.3.2. Mechanism studies The exsisting mechanism studies include: (1) Research on the mechanism and effect of magnetic field, including the study of the trajectory of particles under magnetic field, the study of the capture effect of magnetic field on nanoparticles, the development of a device for detecting the effect of magnetic field targeting, and so on [37,38, 40, 150–157]. For example, De Saint Victor et al. [36] placed a square permanent magnet at the occlusion port of the occluded Y-shaped arteriole bifurcation to enhance microbubble delivery efficiency and evaluate magnetic field targeting effects. Lu et al. [158] placed a cylindrical permanent magnet under the cell culture plate to study the capture of magnetic nanoparticles by the cells, and found that the magnetic field enhanced the capture of magnetic nanoparticles by the cells. Ramaswamy et al. [151,159] studied the movement of nanoparticles in brain tissue by placing brain tissue with magnetic nanoparticles between two permanent magnets with the same magnetization direction. (2) Evaluation of a new established magnetic particle for magnetic drug targeting [32,160–172]. In general, a new kind of magnetic particle needs to be evaluated for its targeted effect, including the magnetic responsiveness of magnetic particles [27–31], the trapping effect of cells on particles [32,33], animal experiments [160, 173–181], and so on. For example, Che et al. [27] verified the magnetic responsiveness of the newly constructed silica nanoparticles by placing a cylindrical permanent magnet next to the nanoparticle container. And use permanent magnetic fields and electromagnetic fields to increase drug targeting efficiency. In Chen et al.'s study, magnetic fields with different intensities (0, 100 or 300 mT) were placed under the culture plate to study the capture effect of cells on magnetic nanoparticles (MNPs) [32]. Venugopal et al. [4] placed a cylindrical NbFeB permanent magnet with a diameter of 5 mm and a height of 2 mm on the back of the rat, and guided the MNPs from the spinal subarachnoid space to the mid-upper thoracic region.

(1) Design of magnet systems. In the design of the magnet systems, the factors to be considered include the type of disease, the location of the lesion site, the type of DDS selected and others. To achieve successful targeting, large BB' (indication of large magnetic force) is necessary. Simultaneously, 3-D precise targeting deep in the body is required. However, localized high magnetic field is not possible using static magnetic field, hence dynamic magnetic field can be the major solution to the problem, otherwise combination with other targeting methods shall be considered. (2) Mechanism studies. The study of the interaction between DDS system and magnetic field, the motion state of DDS under magnetic field, and the mechanism of magnetic field optimization will be helpful to the design of good magnet systems. (3) Preclinical researches. More preclinical animal experiments need to be carried out to verify the targeting effect of the existing magnet systems and find out the deficiencies of the existing magnet systems in clinical application, so as to improve the design. Funding This work was supported by the National Natural Science Foundation of China (Grant No. U1632126), and 921 project of China (Grant No. 17430206). Declaration of interest

More mechanism studies are still beneficial and needed to help in the design and utilization of targeting magnet systems.

None. 4.3.3. Clinical application studies Up to date, the clinical application of magnetic targeting techniques mainly utilizes permanent magnets [11,182–187]. The magnet is placed on the human body surface close to the lesion site, and the magnetic nanoparticles are attracted to the lesion site by the attraction of the magnetic field. As mentioned in the introduction section, the first clinical trial of magnetic drug targeting used a single 0.8 T permanent magnet placed on the skin surface to treat the tumor [15]. In a clinical treatment trial of 4 patients with hepatocellular carcinoma, a cylindrical permanent magnet with a strength of 0.5 T was placed on the skin surface near the tumor [185]. Hence in clinical trials, usually the magnetic targeting techniques are mainly used to treat body surface diseases. Now there have already been many types of magnet systems for drug targeting, but not yet tried in the clinical studies. In the future, efforts to realize clinical studies using magnet systems other than single permanent magnet shall be made, so that the future choices of magnet systems for targeted drug delivery can be expanded.

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