Researchers from the University of Colorado Anschutz Medical Campus have developed a promising new approach to treating urinary tract infections (UTIs) by delivering antibiotics directly into bladder tissue, potentially offering a solution for patients with recurrent infections.
The innovative method, detailed in a recent publication in Nanomedicine, uses intravesically-delivered polymeric nanogels conjugated with a cell-penetrating peptide to transport the antibiotic gentamicin directly to infected cells within the bladder wall.
Targeting Persistent Bacterial Reservoirs
UTIs caused by Pseudomonas aeruginosa are particularly problematic in hospitalized patients with indwelling catheters. While conventional antibiotics can effectively treat bacteria in the bladder lumen, they struggle to penetrate the urothelium to eliminate intracellular bacterial communities (IBCs) that often lead to recurrent infections.
"We believe this new approach offers a more effective treatment by delivering the drug directly to the infected cells, allowing it to precisely target and eliminate the infection," explained co-author Devatha Nair, PhD, an associate professor in craniofacial biology at the University of Colorado School of Dental Medicine. "This method minimizes side effects and reduces the risk of antibiotic resistance."
The nanogel delivery system consists of 2-hydroxyethyl acrylate, tetraethyl dimethacrylate, and acrylic acid monomers, conjugated with a cell-penetrating peptide (Cys-Gly-Lys-Arg-Lys) that facilitates entry into urothelial cells.
Impressive Preclinical Results
In laboratory studies, the nanogel system demonstrated a 36% increase in intracellular gentamicin delivery compared to conventional methods. When tested in an acute UTI murine model, the approach achieved more than 90% clearance of uropathogenic P. aeruginosa.
The drug delivery system maintained maximum release for up to 8 hours, with gradual decline from 12 to 96 hours. Importantly, the nanogels showed minimal toxicity, with no significant effect on cellular metabolism at concentrations up to 1 mg.
"We prove not only that this technology is doable but could be very effective for future clinical use and can potentially lead towards an eventual cure of recurrent infections," said senior author Michael Schurr, PhD, an associate professor in the department of immunology & microbiology at the University of Colorado School of Medicine.
Multidisciplinary Collaboration
The development of this novel treatment approach was made possible through collaboration across multiple departments at the University of Colorado Anschutz Medical Campus. The nanogels were developed in Nair's polymer lab in the School of Dental Medicine, while the peptide was studied in Dmitri Simberg's lab at the Skaggs School of Pharmacy and Pharmaceutical Sciences.
Lead author Humberto Escobedo, PhD, combined expertise in polymer chemistry, pharmacology, microbiology, and urogynecology to create the targeted delivery system. Clinician-scientist and urogynecologist Marsha K. Guess, MD, MS, worked with Schurr's lab to develop and test the approach with an eye toward human applications.
Broader Applications
The researchers note that this nanogel-based drug delivery method could have applications beyond UTIs. The concept originated from the CU School of Dental Medicine as a potential approach for treating periodontal disease.
"This is an exciting advancement for the delivery of medicine and the potential to improve the quality of life for many people," Schurr noted. "For urinary tract infections, they are not only common and costly but also debilitating, severely affecting the quality of life for those who suffer from them."
The study was funded by the National Institutes of Health (NIH) and represents a significant step forward in addressing the challenge of recurrent UTIs, which affect millions of patients worldwide and contribute to the growing problem of antibiotic resistance.
