UCLA team develops method to improve drug efficacy and reduce side-effects
Left to right: Daniel Clemens, Bai-Yu Lee, Marcus Horwitz, Jeffrey Zink, Barbara Jane Dillon and Zilu Li
Scientists from the California NanoSystems Institute at UCLA have developed a nanoparticle delivery system for the antibiotic moxifloxacin that vastly improves the drug’s effectiveness against pneumonic tulaeremia, a type of pneumonia caused by inhaling the bacterium Francisella tularensis.
The study, which appears in the journal, ACS Nano, shows how the nanoparticle system targets the precise cells infected by the bacteria and maximises the amount of drug delivered to those cells.
Professor Jeffrey Zink, lead author of the paper, developed the mesoporous silica nanoparticles used in the process. Zink and his research team conducted an exhaustive process to find the best particle for the job. ‘The nanoparticles are full of deep empty pores,’ Zink said. ‘We place the particles in a drug solution overnight, filling the pores with drug molecules. We then block the pore openings on the nanoparticle’s surface with molecules called nanovalves, sealing the drug inside the nanoparticle.’
When the drug-bearing nanoparticles are injected into the infected animal, the drug stays in the nanoparticles until they reach their target: white blood cells called macrophages. Macrophages ingest nanoparticles into compartments that have an acidic environment. The nanovalves, which are designed to open in response to more acidic surroundings, then release the drug.
‘We tested several different particles and nanovalves until we found the ones that would carry the maximum amount of drug and release it at just the right pH value,’ Zink said. The F. tularensis bacterium is highly infectious and has been designated a top-tier bioterrorism agent by the Centers for Disease control, meaning that it is considered to pose a high risk to national security and public health.
‘F. tularensis survives and multiplies within macrophages, especially those in the liver, spleen and lung,’ said Professor Marcus Horwitz, one of the paper’s senior authors. ‘Macrophages readily devour mesoporous silica nanoparticles, making these particles ideal to treat these types of infections.' Moxifloxacin is a powerful treatment for tularemia, but it has side-effects when administered as a free drug in the bloodstream. The UCLA researchers worked to maximise the efficacy of the treatment while reducing the side-effects.
The study compared the efficacy of freely injected moxifloxacin with that delivered by the controlled-release nanoparticles. In mice given a highly lethal dose of Francisella tularensis, the nanoparticle-delivered moxifloxacin caused fewer side-effects and was more effective at reducing the number of bacteria in the lungs than a higher dose of freely injected moxifloxacin.
The nanoparticle delivery system has the potential to maximise antibiotic effectiveness and reduce side-effects in other infectious diseases, including tuberculosis, Q fever and Legionnaires’ disease.