The use of nanoparticles as carriers of drugs has the potential to revolutionise cancer treatment. Many drugs based on nanobiotechnology are in development and a few are already available. One strategy that has been gaining prominence in recent years is the use of magnetic nanoparticles for targeted drug delivery. Therapeutic anti-cancer drugs are conjugated to the magnetic nanoparticle carrier and are then localised to specific in vivo sites through the use of external magnetic field gradients. The result is that drugs are then released at high concentration in the vicinity of the tumour. This review focuses on the rationale behind magnetic nanoparticle drug design and the physiological and physical obstacles to clinical application. We finish with a review of the new advances in this rapidly growing field.
Background: the rationale behind the use of magnetic nanoparticles in targeted drug delivery
The main challenge in drug delivery specially in cancer treatment is to specifically target the drug to tumour cells at toxic concentrations at an appropriate time. Conventional chemotherapeutic agents have the problems of causing toxicity to some healthy cells and are associated with side effects that can limit their tolerability. Magnetic nanoparticle carriers are currently being developed to overcome these problems to produce site-specific drug delivery. Magnetic nanoparticles loaded with anti-cancer drugs can be injected intravenously or intraarterially into the bloodstream and targeted to a specific region of the body with a high degree of accuracy and at high concentration using external localised high-gradient magnetic fields. The drug can then be held at the tumour site by this magnetic field for the necessary amount of time before the magnetic field is removed and the therapy is completed.
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Nanoparticle drug carriers can produce drug concentrations in the vicinity of a tumour 10 to 100 x greater than free drug alone ( reference to be added ) , resulting in a reduction in the overall amount of the drug that is administered and thus potential side effects. Furthermore these magnetic nanoparticles can be imaged from outside the body, offering opportunities to combine tumour targeting with drug therapy and tumour imaging and diagnostics.
Nanoparticles are excellent at targeting tumour cells because of a distinctive inherent property of solid tumours. Tumour cells are rapidly proliferating and therefore have fenestrated vasculature and poor lymphatic drainage. This results in an enhanced vascular permeability and retention effect (EPR), which allows nanoparticles to accumulate specifically at tumour sites (Maeda et al. 2000). The therapeutic drug is then released from the magnetic carrier once in the vicinity of the tumour through enzymatic activity, changes in physiological pH, osmolality or temperature (Alexiou et al. 2000). Furthermore specific strategies can be used to trigger and therefore tightly control drug release from magnetic nanoparticle carriers, for example, utilising magnetic hydrogels that can switch drug release â€˜on and offâ€˜ by an external magnetic (Liu et al. 2006). Also oscillating the magnetic nanoparticles by external magnetic fields or by using ultrasound waves is another technique currently under study (reference to be added).
Moreover, many techniques are being developed to prevent healthy cells being targeted by nanoparticle-associated drugs. Magnetic nanocarriers loaded with therapeutic compounds can then be specifically targeted to cancerous cells through a number of recognition strategies. Firstly the drug vesicles can be conjugated with nutrients that are required by the tumour cells. In this way the cancerous cells take up the drugs at a faster rate than healthy cells. One example of this is the use of folate-targeted drug technology. Tumour cells preferentially express folate receptors compared with healthy cells and therefore take-up folate-drug conjugates (Leamon C. 2008).
Design of magnetic nanoparticles as drug carriers and obstacles to clinical application
Physiological and physical barriers to drug design
The design of effective magnetic nanoparticle carriers for drug-delivery needs to take many physical and physiological parameters into account. These include magnetic size and properties, magnetic field strength, drug-binding capacity, body weight, tumour site and rate of blood flow (Neuberger et al. 2005).
As described above magnetic targeting works on the principle that magnetic nanoparticle carriers are attracted towards a magnetic field. The magnetic force on the nanoparticle is known as the Lorentz force, and is given by the equation:
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where F is the force (in newtons), E is the electric filed (in volts per metre), B is the magnetic field strength (in teslas), q is the electric charge of the nanoparticle (in coulombs) and v is the instantaneous velocity of the particle (in metres per second).
It is evident from the equation that the important parameters required for capturing the nanocarrier in the magnetic field are the magnetic properties of the nanoparticle and the magnetic field gradient strength. As the magnetic field strength decreases, the ability to capture the particle diminishes, and it is this problem that has hindered the translation of magnetic nanobiotechnology from small animal models to large animals and humans.
Experimental work and mathematical has shown that it is impossible to target a specific tumour site without some degree of spread of the drug to surrounding tissues. This work has also shown that magnetic nanoparticle drug targeting is technically not simple and likely to be most effective for tissues close to the surface of the body and with slower blood flow (Grief and Richardson 2005; Ruuge and Rusetski 1993; Voltairas et al. 2002).
Furthermore, once the drug has been released from the magnetic nanocarrier it is no longer influenced by the externally applied magnetic field. It is then free to resume normal distribution patterns within the body, especially if the drug is released while the nanocarrier particles are still within the vasculature.
Another potentially life-threatening problem with nanoparticle mediated drug delivery is the possibility of embolisation by accumulation of the particles within the vasculature, blocking blood flow. Moreover the particles may accumulate in the liver where they can cause unwanted toxicity. Conversely this phenomenon may be advantageous in the treatment of liver tumours with enhanced targeting of the drug and blockage of the blood supply to the hepatic tumour. ( reference to be added )
Magnetic nanoparticle carrier design
A variety of strategies for the design of magnetic nanoparticles for targeted drug-delivery have been developed. One approach involves a core-shell structure in which the core is a magnetic iron oxide and the shell a polymer such as dextran, silica, PVA or metals such as gold to which therapeutic compounds can be attached via cross-linking (reference to be added). In addition to these polymer nanoparticles, magnetoliposomes have also been developed by a number of groups, which have magnetic iron oxide cores surrounded by an artificial liposome. They are generally used for magnetic hyperthermia treatment but may be used for targeted drug delivery(reference to be added). Nanoparticle drug carriers may also be implanted in hydrogels for triggered drug release upon heating (reference to be added).
More recently gold/cobalt nanoparticles with a core-shell structure have been developed, with the advantage that cobalt has a magnetic moment nearly twice that of magnetic iron oxide(reference to be added).
A further strategy for magnetic/polymer nanoparticle drug carriers involves embedding the nanoparticle within a porous polymer nanoparticle scaffold. One of the advantages of this technique is the ability to produce particles with a spherical morphology and with a relatively limited size distribution (reference to be added).
Others approach is to load magnetic compounds of to a porous crystal ceramic or carbon nanotube of nano size. Biochemical ligands will be attached or absorbed to this particles and drugs can be loaded on them (reference to be added). One group tried to use DNA molecules to attach the drug to the nanoparticles core successfully. The DNA molecule can later be destranded by change of PH and temperature to release the attached drug (reference to be added).