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Pharmacology

Powerful sand

Silica associated to a vaccine induces the organism to produce more antibodies

eduardo cesarAn ordinary substance found in the sea and on rocks, the silica, has shown in tests to have the power to help in the induction of the organism’s defense mechanisms when administered in association with vaccines. “In our studies with mice we saw that the silica used as a means of transportation of the vaccines improved the response of the individuals who produce few antibodies, as well as being non-toxic”, said Osvaldo Augusto Sant’Anna, a researcher at the Immunochemical Laboratory and the scientific director of the Butantan Institute’s Applied Toxicology Center. He is coordinating the project named Immunogenic Complex, developed in partnership with the Cristália Laboratory, a Brazilian company that is wagering on this new development and is investing R$ 250,000 in the tests that can lead to a product.

Called nanostructured silica, it is produced from molecules such as surfactants, organic compounds used in the manufacture of detergents and other materials, which functions as a mold. Silica, also known as silicon dioxide and composed of the elements silicon and oxygen, is added over the surfactants. “The surfactants are removed afterwards by way of exposing the material to high temperatures, in a process known as calcination”, says professor Jivaldo do Rosário Matos, from the thermal Analysis Laboratory of USP’s Chemical Institute, who, in partnership with professor Lucildes Pita Mercuri, from the Analytical Chemistry Department of the Federal University of São Paulo (UNIFESP), is participating in the same research group. They are responsible for the studies on synthesis and the physical-chemical description of the nanostructured silica.

After the calcination process, the material is prepared for application. The silica forms a network with structures in the shape of long tubes, hexagonally disposed, in an arrangement of pores very well organized and uniform, with diameter of around 8 nanometers, a unit of thickness equivalent to a billionth part of a meter. “The uniformity of the pore size is very important for obtaining the results”, explains Matos. Depending upon the disposition of the pores and of their size, the material can have various technological applications, such as catalysts, nanosensors and even serving as a means of immobilizing enzymes, the fixation and liberation of medicines and adsorption (fixation of molecules of a substance on the surface of another substance) of heavy metals and other pollutants found in water.

Promising journey
The project of the development of nanostructured silica as an assistant to antigens, substances capable of inducing the production of antibodies, specific against a toxin or a vaccine when injected into the organism, began inside a bus at the end of 2001. In one of his daily journeys made between the cities of Campinas and São Paulo, professor Osvaldo Sant’Anna was talking with professor Márcia Carvalho de Abreu Fantini, from the Crystallography Laboratory of USP’s Physics Institute, when she told him that she had carried out an X-ray of nanostructured silica, which was esthetically very pretty because it reminded her of a bee’s honeycomb with its perfect hexagons.

Immediately the researcher – who followed the pathway of his great grandfather, the doctor named Vital Brazil, one of the pioneers in research into anti-ophidian serums, the founder and first director of the Butantan Institute – remembered a study carried out at the Immuno-Genetics Laboratory some 20 years previously with another type of silica, colloidal, in a gelatinous form. On injecting the silica in high concentrations into mice, it was verified that the macrophages, the cells of the immunology system responsible for the destruction of foreign bodies, had had their activity blocked. This facilitated the response of the defense mechanism. Thus the project with the new silica began to take shape.

chemistry institute / USPThe arrangement of pores in the form of long tubeschemistry institute / USP

In September of 2004, the study was presented by Márcia Fantini,  responsible for the part of the physical description (structural evaluation) of the project’s materials, at the Solid State Chemistry Congress, held in Prague, Czech Republic, where it was received very well as it dealt with the first study concerning a nanostructure with the potential to be used as a vaccine vehicle. At the beginning of 2005, these studies were presented by professor Osvaldo Sant’Anna during a workshop held at the Butantan Institute. In the audience was professor Regina Scivoleto, a retired pharmacologist from USP, who liked the results considerably and undertook to act as the bridge between the Butantan Institute and the Cristália Laboratory, a company with its head office in the town of Itapira, in the interior of Sao Paulo State. The partnership was sealed with a patent request made in September of 2005. Over the next three years the necessary tests should be carried out to determine the viability of nanostructured silica as an adjuvant, the name given to substances that help in the transportation of antigens.

The results of the tests carried out up until now correspond to the researchers’ and company’s expectations. Mixed in with antigens, the nanostructured silica was tested in the immunization of mice and results compared with the results of the same antigens mixed with other known adjuvants used in vaccines so that the response of the organism occurs in a more efficient manner. “If only a suspension of the virus or bacteria that makes up the vaccine is injected, without any adjuvant, it may or may not work, because a rapid reaction of metabolizing of the substance by the organism occurs that eliminates the protective property of the medicine”, says Sant’Anna.

In the comparative studies, as well as silica, aluminum hydroxide, the only approved transporter for immunization in human beings, was used, as well as oily adjuvants used in animal vaccines, which are extremely potent but cause local inflammations that can lead to a granulomas (a chronically inflamed mass of tissue) and even result in wounds. The silica gave an excellent response to this question, because it did not bring about any skin reaction on the mice. “From what we observed, after the inoculation by way of intramuscular injection a very small hard point remains, which disappears after 24 hours”, says professor Sant’Anna.

Antigens such as the venom of the coral snake, bovine albumin and   others were used in the tests on mice. In all of them the silica functioned as an excellent means of transportation. “It has properties that improve the vaccine’s efficiency. With this we believe that we can produce immunity with smaller quantities of antigen”, says the medical neurophysiologist Eduardo Pagani, the clinical research manager at the Cristália Laboratory. This means that it will be possible to immunize double or triple the number of people with the same quantity of antigen.

New tests will be done with the silica mixed in with a hepatitis A vaccine, commercialized by Cristália, in order to evaluate the immune and inflammatory responses. “The hepatitis A vaccine was chosen as a model because it is efficient and safe”, says Pagani. “If it works with this, then it could work with many others.” If the tests were to confirm what has already been observed, silicone could also substitute the oily adjuvants in the immunization of horses for the production of anti-ophidian and anti-tetanus serums. The toxicology studies, as they are standardized and expensive, will be the company’s responsibility, which will contract a center specializing in toxicology in order to carry out the tests. Only after the ending of this phase will clinical research begin, which consists in administering the new medicine to human beings and observing the effects that it brings about.


The Project
Immunogenic complex formed for vaccine antigens encapsulated by nanostructured meso-porous silica
Modality
Applied Toxicology Center – Research, Innovation and Diffusion Centers (Cepid)
Coordinator
Osvaldo Augusto Sant’Anna – Butantan Institute
Investment
R$ 150,000.00 (FAPESP)
R$ 250,000.00 (Cristália Laboratory)

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