UB Researchers Develop New Inhalable Treatment for TB

By Dirk Hoffman

The study’s findings were published online Jan. 14 in the journal Antimicrobial Agents and Chemotherapy. Jessica L. Reynolds, PhD, associate professor of medicine in the Jacobs School, is senior author on the paper titled “Repeated Pulmonary Dosing of β-Glucan-Chitosan-PLGA Nanoparticles Controls Mycobacterium Tuberculosis in Mice.”

The paper details the development of an inhalable, immunomodulating, biocompatible nanoparticle system encapsulating rifampin, one of the most important TB drugs.

“TB is still one of the world’s deadliest infectious diseases, even though it can be cured. Treatment takes many months and involves multiple drugs that can cause serious side effects,” Reynolds says. “Because of this, many patients struggle to finish treatment, which leads to treatment failure and drug-resistant TB.”

Rifampin works well but has two major drawbacks when taken orally: it can damage the liver and not enough of the drug reaches the lungs, where TB bacteria live, Reynolds notes.

To address this, the researchers developed a new way to deliver rifampin directly to the lungs by inhalation instead of pills by packaging the drug into nanoparticles designed to be breathed in.

The nanoparticles have a biodegradable core that holds rifampin, an outer coating that helps them stick to macrophages and a natural molecule on the surface that both improves uptake by immune cells and boosts immune activity, says Hilliard L. Kutscher, PhD, research assistant professor of medicine, and first author on the study.

“These particles are specially built to go straight to the lungs and be taken up by lung immune cells called macrophages, which are where TB bacteria hide,” he adds. “They are designed to slowly release rifampin over time, to stimulate the immune system to better fight TB, and to reduce drug exposure to the rest of the body, lowering side effects.”

Because the drug stays in the lungs longer using this form of delivery, treatment might only be needed once a week instead of every day, Kutscher suggests.

In the study, the researchers used two different mouse models of TB (one that reflects general TB lung infection, and a second, more severe model that closely mimics human TB lung damage and is harder to treat) to test whether once-weekly inhaled nanoparticles work as well as (or better than) daily oral rifampin in reducing mycobacterium tuberculosis.

“Using both models makes the results more reliable and relevant to human disease,” Reynolds says.

The study found that inhaled nanoparticle treatment delivered rifampin much more effectively to the lungs.

“Compared to taking rifampin by mouth every day, the inhaled nanoparticles kept higher levels of the drug in the lungs for much longer — up to a week after a single dose,” Reynolds notes.

All studies involving Mycobacterium tuberculosis were conducted in a certified Biosafety Level 3 (BSL-3) facility, the standard laboratory environment required for TB research nationwide. These facilities operate under stringent established federal, state, and institutional regulations and include controlled access, specialized ventilation, sterilization, and other validated safety procedures.

Reynolds says, “the work highlights the potential of long-acting inhaled medicines to simplify TB therapy.”

“Reducing treatment frequency could improve adherence, lower side effects, and make TB care more accessible worldwide,” she says.

“These findings support continued development of inhalable, long-acting TB therapies as a promising strategy to improve treatment outcomes and reduce the global impact of tuberculosis.”

Patrick O. Kenney, MD, clinical assistant professor of pediatrics, and co-author on the study, says the potential public health benefits of the research goes beyond tuberculosis.

“Rifampin is not just a TB drug, it is also a key medication for other serious lung infections caused by non-tuberculous mycobacteria, such as Mycobacterium kansasii and Mycobacterium xenopi, which are increasingly recognized in the U.S.,” Kenney says. “These infections often affect people with chronic lung disease and can be difficult to treat.”

Kenney says targeted lung delivery could also potentially solve a long-standing drug interaction problem.

“One major limitation of rifampin is that when taken orally, it strongly activates liver enzymes and this reduces the effectiveness of other important antibiotics, such as azithromycin and clarithromycin which are cornerstones of therapy for Mycobacterium avium/intracellulare complex (MAC) lung disease,” he says. “Because of this interaction, rifampin is often avoided even when it could otherwise help.”

However, by delivering rifampin directly to the lungs instead of the whole body, this approach could: achieve high drug levels where the infection is, minimize drug levels in the bloodstream and potentially reduce harmful drug-drug interactions, Kenney notes.

“That opens the door to using rifampin more effectively in a broader range of pulmonary mycobacterial diseases — not just TB.”

Study co-authors from the Jacobs School are:

• Patrick O. Kenney, MD, clinical assistant professor, Department of Pediatrics
• Hilliard L. Kutscher, PhD, research assistant professor, Department of Medicine
• Arnav Shah, an undergraduate student in biochemistry at UB at the time the work was done, who is currently pursuing a Master of Public Health degree at UB
• Evon Smith, an undergraduate student in biomedical sciences at UB at the time the work was done, who is currently pursuing a master’s degree in the Department of Pathology and Anatomical Sciences
• Maria Tamblin, research technician II in the Department of Medicine