Many of today’s cancer treatments are harmful to healthy body tissue as well as the tumor, and are not specific enough. One example of this is chemotherapy, where the drugs not only kill cancer cells, but also affect other cells in the body that divide rapidly. This applies to cells with a high doubling rate, such as hair cells and bone marrow. The treatment is killing healthy cells at the same time as killing the cancer cells. How can nanoparticles be used in cancer treatment to enhance the effect of today’s methods?
Radiation can be a relatively non-specific method to fight cancer, and standard radiotherapy is limited by the damage of the healthy tissue surrounding the tumor. In other words,when the healthy tissue around the tumor cannot take anymore of the radiation, the treatment has to be put on hold, even if the tumor is not radiated enough to kill all of the cancer cells. This may be improved by injecting hafnium oxide nanoparticles into the tumor before irradiation. Radiotherapy causes reactions with water molecules in body tissue that release free radicals, which in turn harm the DNA in cells and kill them. The injected nanoparticles have a higher electron density than water, leading to more free radicals, i.e. an enhanced radiotherapy treatment. For further information on this treatment, check out the French company Nanobiotix.
Another possible method is to use magnetic nanoparticles in an alternating magnetic field, causing the particles to rapidly switch their magnetic orientation. The result is a rise in temperature, which damages the tumor tissue surrounding the particles. The German company MagForce AG has already looked into this and is currently focusing on the post marketing clinical trial. The method involves a ferrofluid (a liquid strongly magnetized when in a magnetic field) that is injected into the body through a regular cannula. A cannula is a flexible tube with a needle at the end, that is inserted into a vessel to drain fluid or administer medication. The liquid injected consists of nanoparticles made of an iron oxide magnetite (Fe3O4) core that is coated in aminosilane. Each particle has a diameter of approximately 12 nm, and the coating helps the colloidal dispersion of the particles in the aqueous solution. In order for the nanoparticles to have an effect, they have to be applied an alternating magnetic field which can provide a frequency of 100kHz and have a field strength between 2 and 15 kA/m. When the iron oxide cores in the ferrofluid are exposed to the magnetic field, relaxation processes produces heat within the tumor. The tumor cells are either killed directly by the heat, or sensitized so that chemo or radiotherapy may be used with a better result.
The use of nanoparticles combined with an external field has a great potential to improve the way we treat cancer. It has been shown that irradiated hafnium oxide particles release more free radicals than water, hence they are a more effective method than regular radiotherapy. And a ferrofluid in an alternating magnetic field produces enough heat to affect the tumor. But what are the negative effects of injecting metal nanoparticles into a patient?
When injecting metal nanoparticles into our bodies, it is important that they do not interfere with proteins or cause an inflammation – they have to be chemically inert. It turns out that metals we have considered inert can be catalytically active if their diameters are below a certain length (for example for gold: 3.5 nm). To exclude size as a potential threat it is necessary to test the toxicity of the nanoparticles on several size levels.
If the hafnium oxide nanoparticles used in the enhanced radiotherapy accumulated outside the tumor and were irradiated, it would have had a greatly negative effect on the healthy tissue surrounding the tumor. But research shows that less than 10% of the hafnium oxide injected into a tumor had leaked out within the first 14 days. The x-rays still caused free radical reactions in healthy body tissue, but the injected hafnium oxide particles did not enhance the reaction outside the injected areas. This is of importance for further effort in this research field.
It has also been shown that uptake of these nanoparticles by phagocytic cells in the body does not have a significant toxicity on the viability of the cells. By studying cells 13 and 26 weeks after injection of the nanoparticles, they showed no signs of being irritated or contaminated.
Regarding iron oxide particles, research has shown that bare iron oxide has some toxic effects. Lewinski et al. found this in a cell count after injecting uncoated iron oxide nanoparticles, where there was detected reduced cell viability. This was not the case when they coated the nanoparticles with polyethylene glycol (PEG), where the particles were then found to be nontoxic and safe to use in various biomedical applications. The coating chosen for the iron oxide particles also determines how the particles will spread out in body tissue. It has been found that aminosilane coated nanoparticles injected into the tumor spreads out evenly and contributes to a homogeneous heat distribution throughout the tumor, while dextrone coated particles does not spread out in the tumor as desired, and the wanted effect is not achieved. It is obvious that to coat the nanoparticles is essential for biomedical use, and also that what kind of coating one choose is of great significance.
In addition to strict rules to get clinical trials approved, there are several questions that remains to be answered: are the remains of the hafnium oxide nanoparticles harmful to other body tissue in a later stage (weeks, months after the injection)? Can the nanoparticles be stored in the body and have a negative affect years later? And how will the nanoparticles affect the environment as the body disposes of them?
Image courtesy of Nanobiotix.