Inhaled antibiotics have been proposed as efficient treatments to reduce bacterial infections in bronchiectasis patients. Now researchers have shown that a new formulation of antibiotics using nanoparticles, called nanoplex, as a delivery vehicle has advantages compared to previous formulations.
Patients with bronchiectasis are exposed to a chronic inflammatory cycle in their airways, characterized by poor mucus clearance, and a high rate of recurring infections that can lead to lung damage.
Inhaled antibiotics are the current standard care for patients with cystic fibrosis bronchiectasis, with several clinically approved formulations, such as dry power inhalers like tobramycin and colistin, and nebulized aztreonam (these therapies are sold under several brand names).
However, for non-cystic fibrosis bronchiectasis (NCFB), there are no clinically approved antibiotics. This is mainly due to missing data on long-term efficacy and varied outcomes from clinical trials on NCFB patients.
Bayer’s ciprofloxacin — a broad-spectrum antibiotic sold under the brand name Cipro — is the agent that holds the most promise. Clinical evidence shows that it works against Pseudomonas aeruginosa, one of the most prevalent bacteria in bronchiectasis-related infections.
Despite preliminary data showing promising results, the RESPIRE trial failed to get approval from the U.S. Food and Drug Administration, leading researchers to reason that there was room to develop better ciprofloxacin formulations.
Researchers tested an alternative formulation where ciprofloxacin is shaped into a nanoparticle complex — nanoplex.
By comparing ciprofloxacin nanoplex with ciprofloxacin liposomes (the formulation used in the ORBIT trials), the team saw that the nanoplex size (average 306 nanometers) and the ciprofloxacin liposome size (average 196 nanometers) were both able to go through mucus pores. Liposomes are engineered spherical vesicles with a fat (lipid) double layer used as a vehicle to deliver medications.
When the team tested the mucus permeation capacity of the two formulations in sputum (cough material), they saw that both types readily overcame the mucus barrier — after one hour, almost 50 percent of the particles are successfully diffused.
Then, using an artificial medium that simulates NCFB sputum, the team found that ciprofloxacin nanoplex in aqueous suspension form was able to dissolve rapidly and generate a high concentration of ciprofloxacin in the medium. In contrast, ciprofloxacin liposomes showed a sustained release and a lower ciprofloxacin concentration.
Ciprofloxacin nanoplex showed complete dissolution after two hours, while the ciprofloxacin liposomes took eight hours to reach 100 percent dissolution.
Both ciprofloxacin nanoplex and liposomes showed antimicrobial activity against P. aeruginosa in the presence of healthy mucus and mucus from NCFB patients. In dry powder inhaler (DIP) form, ciprofloxacin nanoplex led to a greater antibiotic exposure with a lower antibiotic dose, compared with the liposome formulation.
Toxicity studies conducted in human lung epithelium cell lines showed that ciprofloxacin nanoplex exhibited minimal cytotoxicity, and that the great majority of cells survived the treatment. In particular, ciprofloxacin nanoplex in DIP form showed a cell survival rate of 94 percent for the lowest dose (3.125 milligrams/milliliter), whereas liposomes showed a 76 percent cell survival rate for the same antibiotic concentration.
Overall, the “study showed that the DPI of [ciprofloxacin] nanoplex represented a more viable antibiotic nanoparticle formulation strategy for NCFB therapy than the DPI of CIP liposome,” the team concluded.