Since July 2018, Cevidra has marketed Cevidra® Calixarene, the first emergency local treatment for skin contamination by actinides (such as uranium, plutonium, americium, etc.). The treatment, a simple-to-use cleansing cream, prevents uranium from passing through the skin barrier by more than 95% if applied immediately, and was developed during two theses in IRSN's Radiochemistry, Speciation and Imaging Research Laboratory (LRSI) in partnership with the Institut Galien Paris-Sud (UMR CNRS 8612) and the Defense Procurement Agency (DGA).
Previously, the only treatment available was an emergency rinsing with soapy water, which was not very effective. This cleansing cream consists of a nanoemulsion with the active ingredient calixarene carboxylic acid (1,3,5-OCH3-2,4,6-OCH2COOH-p-tertbutylcalixarene), which traps actinides, notably uranium. It therefore prevents them from passing into the bloodstream, where they can become attached to the kidneys and bones, causing a risk of pathologies developing in these organs over time. The marketing of the cleansing cream is the culmination of 10 years of research by the LRSI and the Institut Galien Paris Sud.
Use of calixarenes
The calixarenes of interest are from a family of molecules which have a strong affinity for actinides, such as uranium, due to their complexing function (carboxylic or hydroxamic acid) and their geometry. They are used in the field of radiotoxicology to analyze and extract actinides from biological media (such as urine, stools, etc.) or the environment.
They were already considered for use in medicine in the 1990s for internal decontamination from uranium, through the intravenous injection of two sulfonic calixarenes. Yet, with tests showing these two molecules to be hepatotoxic, the use of calixarenes in decontamination treatments was ruled out for a long time.
However, in the absence of an effective treatment against uranium contamination, IRSN decided to revisit calixarenes for use in decontamination treatments, but this time only in the case of external contamination through direct skin contact.
Developing the nanoemulsion
The main challenge in using calixarenes as a decontamination treatment was to find a galenic form (form through which an active ingredient is administered) that prevents the absorption of calixarenes by the skin and allows the maximum amount of uranium to be trapped.
The calixarenes used are liposoluble molecules (soluble in an organic environment such as oil). The idea was therefore to develop a nanoemulsion of oil in water to be applied to the skin. The active ingredient of the nanoemulsion, calixarene carboxylic acid (1, 3,5-OCH3-2,4,6-OCH2COOH-p-tertbutylcalixarene), was chosen for its suitable spatial structure, which causes the molecule to become positioned on the surface of the oil droplets while keeping its complexing groups, which interact with uranium, free in the aqueous phase (see Figure 1). The uranium molecules become trapped on the surface of the oil droplets, which are too large to be absorbed by the skin. This work was done during an IRSN thesis defended in 2009 that developed the nanoemulsion and proved its efficacy in vitro and ex vivo on pig ear skin explants, which are very similar to human skin. The thesis also has a patent pending, which covers the use of all kinds of calixarene-based formulae for actinide decontamination.
Figure 1: Calixarene nanoemulsion
Work on a galenic form
Following the thesis, a first version of the nanoemulsion, in liquid form, was presented to several occupational health physicians working in the Orano Group (previously Areva) in the nuclear field. Thanks to their feedback and inside knowledge of the risks incurred by nuclear workers, other, better performing, galenic forms were developed:
a cleansing form for application on a large surface of the skin and on specific areas, such as the hair and scalp;
and a gel form to be applied to damaged skin.
Also in partnership with the Institut Galien Paris Sud and the DGA, a second thesis, defended in 2015, confirmed the efficacy of the nanoemulsion ex vivo and in vivo and ensured the in vitro non-toxicity of calixarene in all its galenic forms.
The ex vivo experiments performed show that uranium diffusion through the skin is reduced by 95% when the nanoemulsion is applied immediately after contamination. The tests also showed that it is still significantly effective when applied 30 minutes later, and 71% of uranium is blocked from passing through the skin. The in vivo study on rats demonstrated that applying the nanoemulsion reduced the concentration of uranium attached to their femurs and kidneys by 85% and 95% respectively. The toxicity assessment on in vitro reconstructed human skin showed no skin irritation, damage or inflammatory effects, even after an extended application of 24 hours.
Industrial development and marketing
In 2016, IRSN signed a partnership with the Cevidra laboratory with a view to the clinical application and industrial development of the nanoemulsion. The choice was made to market the cleansing form first, since it was simpler to use and more universal. The study on the safety of the nanoemulsion was continued with additional tests on human skin explants and in vivo studies on other animal models as part of a clinical application as a Class I medical device (low risk). The partnership confirmed the efficacy of calixarene on an industrial level, leading the French National Agency for Medicine and Health Product Safety (ANSM) to grant authorization to place it on the market. The Cevidra® Calixarene cleansing cream was presented at the World Nuclear Exhibition in Paris on 26 28th June 2018, where it won the prize for nuclear safety innovation.
Additional studies are in progress to verify its efficacy on cesium, cobalt and strontium, in order to widen the scope of its application. The first results will be presented at the International Conference on the Health Effects of Incorporated Radionuclides (HEIR) taking place on 8-11th October 2018 in Fontenay-aux-Roses.