The future of tuberculosis therapy is changing with nanoparticles delivering drugs direct to the lungs, according to new research

Karlsruhe Institute of Technology and Research Center Borstel researchers have presented their work on nanoparticles with a high antibiotic concentration for inhalation – nanocarriers of antibiotics that can reduce resistances and enhance compatibility.

Tuberculosis is the infectious disease with the highest death rate worldwide.

As reported by the WHO, therapy-resistant tuberculosis infections are increasing. Diseases due to this bacterial infection may also occur in Germany.

Tuberculosis represents a special challenge for two reasons: First, the bacteria encapsulate in tissue, mostly in the lungs, where they may be inactive for years and cause symptoms long after the primary infection.

Second, tuberculosis bacteria are often resistant against two or more common antibiotics.

Increasing occurrence of therapy-resistant strains is caused by insufficient drug concentrations at the place of infection and a premature termination of the treatment due to the often severe side effects of the antibiotics.

A nanomedical approach can help to reduce the development of further resistances.

Nanoparticles will be used to carry new antibiotics directly to the source of infection and infected cells. In this way, drug concentration may be increased locally in the lungs.

Professor Claus Feldmann, head of a research group at KIT’s Institute for Inorganic Chemistry (AOC), explained: “However, newly developed antibiotics often are lipophilic and fat-soluble and cannot or can hardly be administered in water.

“They can hardly be absorbed when contained in the stomach, blood, or cell fluid.”



New nanocarriers


Presently, patients suffering from tuberculosis are treated with high doses over a long time in order to have the pathogens reach the foci of infection.

The partly severe side effects, such as liver damage, often cause termination of the therapy, as a result of which further resistances develop.

In future, nanoparticles will be used for the specific delivery of antibiotics.

Professor Ulrich E Schaible, head of the Cellular Microbiology Group and director of the Research Center Borstel, Leibniz Lung Center, said: “We have already tested several nanocarriers for transporting antibiotics to the tuberculosis pathogens in mice.

“The new nanocarriers developed by our colleagues at KIT [have] convinced me that it is possible to directly deliver high doses of antibiotics to the foci of tuberculosis in the lungs without affecting other organs.”

Researchers at KIT’s Institute for Inorganic Chemistry have succeeded in producing nanoparticles with extremely high concentrations of antibiotics.

Feldmann said: “Concentration of the antibiotic is up to 99% of the total weight of the particles.

“According to literature, a maximum of 10% only has been usually reached so far.”

The KIT-made nanocarriers can be dispersed in water. When inhaled, the aerosol enters the depth of the lungs.

At the Research Center Borstel, researchers under the direction of tuberculosis expert Schaible, in co-operation with other partners from Germany, Austria, and Belgium, tested the effectiveness of the nanoparticles with good results in both the lab and the living organism.

Work was carried out within the ANTI-TB project funded by the Federal Ministry of Education and Research (BMBF). Meanwhile, KIT and the Research Center Borstel have applied for a joint patent.

Schaible advised: “Still, a lot of work will be needed until this aerosol formulation can be applied to humans.”

The amorphous nanoparticles for inhalation contain a Bedaquilin concentration of 69% or a BTZ-043 concentration of 99%.

Both antibiotics are effective against multi-resistant tuberculosis bacteria.

Surfactants make the highly lipophilic antibiotics disperse in water. Dispersions with 4.0 mg of Bedaquilin / ml or 4.2 mg BTZ-043 / ml remain stable for several weeks.

When tested in mice, the effectiveness of nanoparticle dispersions exceeded that of conventional BTZ-043 solutions for pulmonary inhalation by 50%.

The nanocarriers proved to be capable of overcoming various biological barriers. High concentrations were measured in the lungs, but not in the liver and spleen.

The research is published in ACS Nano.

Image: Microscopy of a lung section of a TB-infected mouse with the drug nanoparticles coloured red. Credit: FZB Zelluläre Mikrobiologie, Dr. N. Redinger.

Research Aether / Health Uncovered