Scientists have identified for the first time a mechanism by which nanoparticlescause lung damage and have demonstrated that it can be combated by blocking theprocess involved, taking a step toward addressing the growing concerns over thesafety of nanotechnology.
Nanotechnology, the science of the extremely tiny (one nanometre is one-billionth ofa metre), is an important emerging industry with a projected annual market of aroundone trillion US dollars by 2015. It involves the control of atoms and molecules tocreate new materials with a variety of useful functions, including many that could beexceptionally beneficial in medicine. However, concerns are growing that it may havetoxic effects, particularly damage to the lungs. Although nanoparticles have beenlinked to lung damage, it has not been clear how they cause it.
In a study published online today (Thursday 11 June) in the newly launched Journalof Molecular Cell Biology [1] Chinese researchers discovered that a class ofnanoparticles being widely developed in medicine - ployamidoamine dendrimers(PAMAMs) – cause lung damage by triggering a type of programmed cell deathknown as autophagic cell death. They also showed that using an autophagy inhibitorprevented the cell death and counteracted nanoparticle-induced lung damage inmice.
"This provides us with a promising lead for developing strategies to prevent lungdamage caused by nanoparticles. Nanomedicine holds extraordinary promise,particularly for diseases such as cancer and viral infections, but safety concernshave recently attracted great attention and with the technology evolving rapidly, weneed to start finding ways now to protect workers and consumers from any toxiceffects that might come with it," said the study's leader, Dr. Chengyu Jiang, amolecular biologist at the Chinese Academy of Medical Sciences in Beijing, China.
The first nanomaterial was developed by German scientists in 1984. Nanomaterials are nowused in a variety of products, including sporting goods, cosmetics and electronics. The factthat unusual physical, chemical, and biological properties can emerge in materials at thenanoscale makes them particularly appealing for medicine. Scientists hope nanoparticles willbe able to improve the effectiveness of drugs and gene therapy by carrying them to the rightplace in the body and by targeting specific tissues, regulating the release of drugs andreducing damage to healthy tissues. They also envision the possibility of implantable nanodevices that would detect disease, treat it and report to the doctor automatically from insidethe body. The US Food and Drug Administration has approved some first generationnanodrugs. One example is Abraxane, a nanoformulation of the anti-cancer chemotherapypaclitaxel.
Lung damage is the chief human toxicity concern surrounding nanotechnology, withstudies showing that most nanoparticles migrate to the lungs. However, there arealso worries over the potential for damage to other organs.
In the study, the researchers first showed, through several independent experiments,that several types of PAMAMs killed human lung cells in the lab. They did notobserve any evidence that the cells were dying by apoptosis, a common type ofprogrammed cell death. However, they found that the particles triggered autophagiccell death through the Akt-TSC2-mTOR signalling pathway. Autophagy is a processthat degrades damaged materials in a cell and plays a normal part in cell growth andrenewal, but scientists have found that sometimes an overactivity of this destructionprocess leads to cell death.
The researchers also found that treating the cells with an autophagy inhibitor knownas 3MA significantly inhibited the process, increasing the number of cells thatsurvived exposure to the nanoparticles.
"Those results, taken together, showed that autophagy plays a critical role in thenanoparticle-induced cell death," said Dr. Jiang.
The scientists then tested their findings in mice. They found that introducing the toxicnanoparticles significantly increased lung inflammation and death rates in the mice,but injecting the mice with the autophagy inhibitor 3MA before introducing thenanoparticles significantly ameliorated the lung damage and improved survival rates.
"These experiments indicate that autophagy is indeed involved in lung damagecaused by these nanoparticles and that inhibition of this process might havetherapeutic effects," Dr. Jiang said. "We will likely need to look for additional newinhibitors to block lung damage as this particular compound is not stable in humans,but this gives us a promising lead for the first time."
"Our study has identified the principle for developing such compounds. The idea isthat, to increase the safety of nanomedicine, compounds could be developed thatcould either be incorporated into the nano product to protect against lung damage, orpatients could be given pills to counteract the effects," Dr. Jiang said, adding that thefindings could also provide important insight into how nanopaticles cause other toxiceffects.
It is not clear whether other types of nanoparticles would cause lung damage via thesame mechanism, but some may, Dr. Jiang said. The group's research alsosuggests that blocking autophagic cell death could perhaps be useful in combatingother causes of lung damage.
Source: Oxford University Press