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= The Use of Magnetic Nanoparticles in Drug Delivery = Magnetic Drug Delivery involves exactly what you think it would involve. The concept surrounds the use of external or internal magnets to increase the accumulation of therapeutic elements in nanoparticles to fight pathologies in specific parts of the body. This Wikipedia page discusses previous, current, and future knowledge and work surrounding the subject.

Furthermore, magnetic drug delivery is one of the largest aspiring forms of improving drug delivery in the 21st century. An influx of new studies in the field are continuously bringing an increased knowledge regarding the topic; researchers are noting the potential in the field. In the field of drug delivery, finding ways of increasing the concentration of therapeutic elements at the exact point of disease is very important to a patient's disease course. A common drawback of systemic drug delivery is side effects due to accumulation of drugs on the complete other side of the body. Thus, there has been an increase in emphasis on systemic drug delivery being focal via a novel amount of mechanisms, where magnetic drug delivery is one of the most promising of such. The use of magnetic drug delivery can have many applications in clinics involving mostly tumor/cancer treatment, but also ocular/brain delivery, cardiovascular disease and even diabetes. Consequently, magnetic drug delivery can be useful in clinical situations for the treatment of a patient’s disease state with further research and clinical trials.

A Brief Background of Magnetic Drug Delivery
The development of magnetic nanoparticle drug delivery started with Paul Ehrlich’s concept of a “magic bullet” that would destroy only the target organism. The concept was built upon during the 1970s with the application of the anticancer drug doxorubicin in animal models. Most of the research discoveries following were successful. However, they were not able to cross over into the clinical setting due to some of the disadvantages such as a high concentration of nanoparticles accumulating in the liver. The first successful clinical trials involving magnetic nanoparticles occurred in 1996 which drastically increased the scientific interest in magnetic nanoparticles. Before these successful clinical trials, there were less than 100 scientific articles published mentioning magnetic nanoparticles. However, since the publishing of these successful clinical trials there has been an exponential increase in research surrounding magnetic nanoparticles with thousands of scientific articles mentioning magnetic nanoparticles being published annually by 2020.

Tumor hypoxia is an important condition regarding tumor growth. It is defined by the highly proliferating mass of cells in a tumor growing too fast for the vasculature to keep up, causing an environment void of oxygen. This hypoxia is thought to reduce chemotherapy effectiveness as there is a decrease in oxygen free radicals that produce DNA damage and cell death. This also induces difficulty for drug administration that uses the circulatory system. The delivery of therapeutic elements is difficult without vasculature. The environment tumors create has driven considerable attention towards magnetic nanoparticles as a possible form of drug delivery for tumors. Fundamentally, as mentioned before, use of magnetic nanoparticles for drug delivery involves the accumulation of therapeutic elements at a disease site to increase their therapeutic effects as well as limit side-effects on other parts of the body. There are many factors involved with this that act as variables to accumulation. This includes blood circulation, adherence of therapeutic elements, diffusion ability of therapeutic elements, bodily response to increased concentrations of these particles, etc. In a study done by Hirota et al., the researchers set out to explore the fundamentals of these variables and attempt to explore them artificially and sincerely within rats. This study mentions how traditional drug delivery systems set out to control diffusion and optimization of therapeutic particles, showing how magnetic drug delivery is a whole different ball game. In its artificial component, the Hirota et al. group created pulsatile artificial capillaries for evaluation and used magnetite for its evaluation. Characteristics of this magnetite suspension were made to mimic that of blood. The accumulation of this magnetite ferromagnetically on magnets placed downstream and upstream were used to evaluate the fundamentals of magnetic drug delivery. It was found that downstream placement of the magnet had lower accumulation than upstream. This is critical for evaluation and may be important on a macroscale in further studies. This shows that flow force inhibited accumulation on the magnet downstream but magnetic force of the upstream magnet overcame the force of flow to have larger accumulation. Further work by this team came to the theory that for near-surface disease states, magnets should be placed downstream and that for intra-surface disease states, magnets should be placed upstream for maximum accumulation. For its non-artificial component, this study used an external neodymium magnet over a rat’s liver and injection of magnetite into the portal vein of the rats. The portal vein is involved in chief blood flow to the liver for filtering and other processes. The rats’ livers were extracted, and cut into thin slices for evaluation. Observation of this experiment showed that magnetite accumulated up to 5mm away from the magnet. This rudimentally showed the ability to use magnetic particles for accumulation at certain points of the body with an external magnet.

Characteristics of Magnetic Nanoparticles for Drug Delivery
Characteristics of nanoparticles can be extensively different. It is important to remember that different therapeutic agents may require different nanoparticle characteristics for effective therapeutic application. The main categories of magnetic nanoparticles used currently are metal nanoparticles, metal alloy nanoparticles, and metal oxide nanoparticles. Some key properties of magnetic nanoparticles include having a large specific surface area, excellent biocompatibility, the ability to not cause disease or elicit an immune response, and in some nanoparticles super-paramagnetism. Magnetic nanoparticles are influenced by an external magnetic field due to the magnetic moment found within the network unit. The external magnetic field is necessary for transport and for activation of these magnetic nanoparticles, as when the external magnetic field disappears, they become inactive particles. Therefore, when a drug is attached to magnetic nanoparticles, these particles will be targeted using a heterogeneous external magnetic field to guide and concentrate the drug at desired areas. Design of magnetic nanoparticles for clinical application requires careful evaluation of the effect of surface modification, size, shape on its magnetic properties. Considerations of each design parameter must be implemented before overcoming biological barriers and exhibiting function. In Hirota et al., they relied on the use of ferromagnetic properties of nanoparticles for fundamental studies of magnetic drug delivery systems. This is important, as ferromagnetism is described as the coercivity of particles to form macromaterials on permanent magnets. These include iron, cobalt and nickel. These types of base materials can be very important when discussing magnetic drug delivery systems because they also retain their magnetic properties when a magnet is removed; this is why they stick together on the permanent magnets. Iron oxides, such as Fe₂O₄ and Fe₃O₄, in particular play a key role in magnetic nanoparticle drug delivery. The particle sizes typically range from 3 nm to 30 nm and their size distribution is approximately 10-20%. These small sizes have advantages and disadvantages, which will be discussed further below. Overall, these iron oxides display good magnetic properties, lower toxicity, and high stability against degradation.

One example comes from Liang et al., where researchers used superparamagnetic iron oxide (SPIO), polyethylene glycol (PEG) and doxorubicin in its research study surrounding magnetic nanoparticles. The characteristics of the SPIO are important. This carrier of doxorubicin contains the magnetic portion of this combination. Thus, nanoparticle drug carriers of this type can be influenced by outside magnetism. It was found in vivo that SPIO under a magnetic field would lead to greater tumor accumulation of therapeutic elements. In an experiment where one group received SPIO-PEG-D in a magnetic field and the other just SPIO-PEG-D, results showed lower tumor size, reduced cardiotoxicity and hepatotoxicity in the magnetic field. This is crucial, as doxorubicin is known for being extremely toxic and showed the potential for use of a nanoparticle carrier for reduced toxicity in the periphery. SPIO is one of many magnetic nanoparticles that can be used as therapeutic carriers.

Magnetic Nanoparticle Coating
When looking at the use of magnetic nanoparticles in drug delivery, an important aspect is the choice of coating. This defines the biocompatibility of the therapeutic agent. When the agent is not biocompatible it will quickly be excreted from the body and you will not receive magnetic accumulation or the therapeutic effect. The use of organic or inorganic coating molecules increases the half-life of the nanocarrier by delaying its clearance by the reticuloendothelial system (RES). This delay occurs because the coating overcomes the pH, hydrophobicity, and surface charge of the magnetic nanoparticles. Additionally, coating allows molecules to covalently bind to specific molecules, such as ligands, proteins, or antibodies, which provides binding specificity to target tissues. A common structure of coating includes the core-shell structure. In this structure, metal oxides are coated with biocompatible materials which is efficient, as this allows better control and easier preparation. The most common coatings used with optimum response involve the use of polysaccharides like dextran and polymers like polyethylene glycol. Carbon coatings have been used in recent studies that have been proven biocompatible and with high capacity for absorption into cells. Further studies have shown that even polyaniline with anti-cancer agent epirubicin can be used for tumor exploration of the brain. This was done using ultrasound and magnetic particles, showing a synergistic delivery style. Finally, another generalized coating found to have some promise is polyethyleneimine which showed high cellular accumulation and low toxicity. However, it was found to have poor pharmacokinetic properties by its lonesome, but with magnetic field induction it was found to accumulate on tumors well. Additionally, there are various coatings used to prevent leaching of the magnetic core of the nanoparticles. The coatings have a significant salt concentration with a slightly alkaline pH in most cases. There are also silica coatings that increase the external surface area to assist in binding and are heating resistant.

Choosing the right coating for a particular drug to target a specific tissue in the body is important in magnetic nanoparticle drug delivery. In the study done by Liang et al., the researchers used the common cancer treating drug Doxorubicin (Dox). By itself, this drug is extremely toxic to cardiac muscle. Thus, the researchers used super-paramagnetic iron oxide (SPIO) as a nanocarrier of therapeutic Dox. SPIO has magnetic properties but has a very small half-life within the body. One such biocompatible targeting modality to combine these with is polyethylene glycol (PEG). This coating prevents opsonization on the surface of the particles and increases circulation time from minutes to hours or days. This is an established process and shows how hydrophilic PEG interacts beneficially with the physiological environment to improve biocompatibility. Consequently, this opens the door to lots of research regarding hydrophilic coatings to therapeutic element combinations. Particularly, in this MRI study by Liang et al. it was found that PEG prolonged circulation and SPIO-PEG-D particles accumulated more within the tumor with magnetic guidance.

Coating not only provides hydrophilic and hydrophobic characteristics, but it can also provide temperature- and pH-dependent properties. In a study conducted by Pourjavadi et al., the researchers used poly(N-isopropylacrylamide)-co-glycidyl methacrylate (PNG) to coat Fe₃O₄@SiO₂ magnetic nanoparticles to deliver doxorubicin (DOX), an anticancer drug. This coating has a dual pH- and thermo-responsive properties that makes it particularly unique and efficient at delivering DOX. In vitro research analyzed the drug release at pH values of 5.4 and 7.4 (physiological pH) and temperatures of 25 °C and 37 °C (body temperature). The in vitro results displayed higher amounts of DOX release at 37 °C due to the core-shell coating collapsing, which accelerated the release. Additionally, lower amounts of DOX was released at physiological pH, which is most likely due to the nanocarrier surface stability, allowing for greater control.

Similar results involving magnetic nanoparticle coating pH-dependent behaviors were observed in a study conducted by Ding et al. A hydrogel composed of chitosan crosslinked to a carboxymethyl-beta-cyclodextrin polymer coated a Fe₃O₄ magnetic nanoparticle to deliver the hydrophobic anticancer drug 5-fluorouracil. The chitosan functions to open tight junctions located between epithelial cells, which favors drug transport into target cells. Chitosan is hydrophilic, however, so the carboxymethyl-beta-cyclodextrin polymer provides a hydrophobic layer to enable solubilization of 5-fluorouracil. In vitro, this coated magnetic nanoparticle displays a swelling effect at acidic pH values, resulting in a higher release rate of 5-fluorouracil, while slower release was observed at physiological pH. This effective transport and controlled release due to the proper coating choice has led these researchers to believe that this magnetic nanoparticle can have promising effects in delivery of this anticancer drug.

Advantages of Magnetic Nanoparticles in Drug Delivery
Magnetic nanoparticles have many unique characteristics that contribute to their success in efficiently delivering drugs to target tissues. The small sizes of magnetic nanoparticles allow them to target a variety of targets of different sizes for different purposes. These sizes range from targeting a small cell (10-100 μm), a virus (20-45 nm), a protein (5-50 nm), or a gene (2 nm wide and 10-100 nm long). If these magnetic nanoparticles are coated correctly, they can interact with and enter structures, allowing adequate delivery of a drug. Additionally, using magnetic nanoparticles in drug delivery has remote control capability. This occurs through the external magnetic field gradient that is associated with the magnetic field’s permeability within human tissue. With the remote control applied, this allows the accumulation and transfer of the magnetic nanoparticles, which has been especially useful in the delivery of anticancer drugs to specific tumor tissues.

Another large advantage of drug delivery using magnetic nanoparticles is the personability of magnet placement depending on disease state location. While this may also be a limitation, it can be greatly effective if the resources are around for personally tailored medicine reception. Additionally, a major advantage of magnetic nanoparticles is that they can be visualized with ultrasound and/or MRI imaging. The cell viability studies conducted by Liang et al. in vitro show promise in magnetic drug delivery as an MRI contrast agent. The increased cellular uptake of SPIO-PEG-D was proven to lead to distinguishable darker differences in MRI. This shows promise for better monitoring of tumor sites with MRI and creates a non-invasive option to detect the nanoparticles in a patient’s body. With the increased SPIO-PEG-D at a tumor site, researchers were better able to visualize tumors, showing potential effectiveness as a contrast agent.

Limitations of Magnetic Nanoparticles in Drug Delivery
Limitations of magnetic drug delivery can range from their inherent magnetic characteristics to interactions with bodily barriers. External body barriers include the immune system. When magnetic nanoparticles are in the bloodstream they have high soluble heterogeneity and ionic strength, allowing them to interact with plasma proteins, stimulating the immune system to further stop their function. Additionally, the proportion of the nanoparticle size to the target tissue has shown limitations in effective drug delivery, especially in the kidneys and the brain. Intracellular barriers include the removal of the magnetic nanoparticles from the target membrane by ligand-dependent endocytosis followed by separation via acidification in the endosome chamber. When designing effective magnetic nanoparticles with proper coating, it is important to consider these limitations. Other barriers to consider are the depth of the target tissue, vascular sources, body weight, the speed and amount of blood flow in the target tissue, distance from the field source, injection route, and tumor volume. However, research has shown that the use of magnetic nanoparticles is more effective when used in near-surface tissues that have slower blood flow.

In the study conducted by Hirota et al., they noted a few limitations to the use of magnetic nanoparticles in drug delivery. One limitation involved the accumulation of particles only 5mm from their external magnet. While there are many variables involved in this experiment that could be different on a macroscopic scale, it is important to note that 5 mm of accumulation may not be sufficient in larger applications of magnetic drug delivery. This may be effective enough for sites close to the surface of the body, but when the site of interest is deep within tissue then the advantage of using magnetic nanoparticles for delivery falls exponentially. It has even been proposed to implant magnets within the body to overcome this limitation. Additionally, this research group theorized that depending on the location of the disease state, magnet use for maximum accumulation can be different for upstream or downstream placement of the magnet. This can be a large limitation in terms of human medicine. Exact locations of disease state and trained operatives would be needed for maximum therapeutic agent accumulation and minimization of side effects.

Another question arises from the subject of cellular uptake. While the use of a magnetic field may guide particles to therapeutic sites, it is not an indicator of cellular uptake of particles. This begs the question if our therapeutic element will have any effect on the effector area. In general, nanoparticles are excellent at crossing cell barriers, however, this may change in the presence of other processes. Promise has been shown with one example of SPIO-PEG-D in research done by Liang et al. Their hydrophilic coating of PEG, an already established biocompatible coating, showed enhanced cellular uptake at tumor cells with a magnetic field in place in vitro. These findings show cellular uptake can even be increased with just a magnetic field. However, this is just one type of therapeutic agent and cannot be applied to all.

Finally, there is a concern that magnetic nanoparticles may be toxic to the body. It is difficult to say for certain that all magnetic nanoparticles are toxic due the large variety of magnetic particles that can be used. The nanoparticles size, biodegradability, composition, and dosage are a few of the characteristics impacting this downside. However, it is shown that magnetic nanoparticles that are inhaled enter the lungs or are swallowed and enter the gastrointestinal tract have unsatisfactory impacts on the body. PEG, linear neutral polyether, coatings have a tendency to lose their targeting capabilities due their “immune stealthing” function. Furthermore, the use of cancer drugs is often extremely toxic. While magnetic nanoparticles work to reduce this toxicity, it is worth noting that it is impossible to predict the overall toxicity of these therapeutic agents while being used in vivo. While nanoparticles show promise, especially when combined with hydrophilic coatings, to accumulate at tumor sites, we may never fully be able to predict side effects elsewhere in the body because it is impossible to guide all nanoparticles to the tumor entirely or to the therapeutic site.

Current Applications
The majority of magnetic nanoparticle use in the clinical setting is for cancer therapies. The magnetic nanoparticles ability to target the specific location of the tumor in the body, a decreased amount of the drug used to treat the tumor, and a decreased amount of the drug impacting the non-target sites. An active method where the magnetic nanoparticles deliver the drug to the tumor but does not act on the non-target tissues. The most commonly tested method of getting the magnetic nanoparticles into the body is through intravenous injection where they will travel through the bloodstream. They eventually make it to their target site with the use of external or implanted magnetic forces. Although the primary focus is cancer, there are also a few applications for magnetic nanoparticle drug delivery for cardiovascular diseases. Atherosclerosis cardiovascular disease is a buildup of plaque in the inner lining of the arteries and there are models on how magnetic nanoparticle drug delivery could be used as a treatment. However there are not any in vivo or in vitro studies of magnetic nanoparticles being used to deliver drugs to the arteries to effectively reduce inflammation.

In the research paper by Nori, et. al, a Fe3-δO4 core-shell was designed as a carrier for drug delivery. The designed magnetic nanoparticle based structure showed many benefits such as biocompatibility, the formation of a covalent bond between the carrier and drug, and glutathione-responsive drug release (prevents early drug release and increases bioavailability). Furthermore, the presence of magnetic nanoparticles in this drug delivery method allowed for its response to external magnetic fields for functionalization.

In the study by Zhu et. al, a pH/magnetic field dual responsive drug loaded nanomicelle was developed for targeted magneto-thermal synergistic chemotherapy of cancer. In this drug delivery system, once the delivery system reaches the target site and tumor cell uptake is complete, an external magnetic field is applied causing a magneto-thermal effect raising the tumor cells’ temperature and further promoting drug uptake. This nanocarrier system aims to improve drug stability, controlled drug release, and tumor targeting efficiency. The results of this experiment showed that this nanocarrier system showed significantly increased treatment efficacy over traditional chemotherapy and did not demonstrate any noticeable biotoxicity in cellular and animal experiments.

The use of nanoparticles in ophthalmic drug delivery is also being explored in the field of clinical research. The nanoparticles were inserted into rats’ corneas or were administered in an eye drop solution. The nanoparticles showed high adhesion to the target site but the exact way that the adhesion occurred is still being researched further. When the rats were exposed to a bacterial substance that should induce keratitis of the cornea the amount of inflammation the rats that were in the treatment group received the eye drops after exposure was inhibited. Other studies have used magnetic nanoparticles in MRI imaging, hyperthermic therapy of cancer, cell purification, biosensing, and immunocytochemical tests. Overall, there is still more research to be done to know if these findings are applicable to humans.