Development and optimization of a nitric oxide releasing microparticle formulation for the topical treatment of chronic rhinosinusitis

Chronic rhinosinusitis (CRS), defined by persistent inflammation and/or infection of the nasal cavity and paranasal sinuses, has a prevalence of 3.6% in the United States adult population, equating to approximately 13 million affected individuals.1,2 Symptoms include nasal obstruction, facial pressure, nasal drainage, and hyposmia.3,4 Bacteria implicated in the pathogenesis of CRS can form biofilms, which are communities of bacteria that coordinate behavior through quorum sensing—a cell density-dependent signal transduction process—to proliferate.25 Increasing evidence suggests that biofilms play an important role in the etiology and morbidity of CRS.26-30 Gram-negative organisms, including PA, are potent biofilm formers and are frequently observed in treatment-resistant CRS.31,35,36 Biofilms, in contrast to planktonic bacteria, harbor unique characteristics that imbue them with a 10-1000 fold higher resistance to antimicrobials. In an evaluation of patients with medially recalcitrant CRS, biofilms were associated with: (i) worse CRS symptom score, (ii) worse radiologic appearance, (iii) recurrent infections, (iv) increased need for surgical intervention, and (v) in those undergoing sinus surgery, poorer surgical outcomes versus non-biofilm CRS.41-43 In many cases, treatment using conventional antibiotics would require a 60-1,000-fold increase in dose, which would be clinically unsafe.44 Topical antibiotic treatment, such as mupirocin nasal irrigations, can be more effective in biofilm treatment, but have demonstrated only short-term efficacy.45,46 Consequently, there is a pressing need for more effective antibacterial therapies in CRS. The goal of this proposal will be achieved through two interconnected specific aims. Specific Aim 1: For clinical-translation purposes, zMP-NO.2 will be synthesized and characterized prior to being evaluated for in vitro antibacterial activity against P. aeruginosa and other bacterial strains relevant to CRS as well as for preliminary cytotoxicity. Specific Aim 2: The concentrations of zMP-NO.2 in a gel vehicle required to deliver sufficient NO to the sinus epithelial tissues to achieve bactericidal activity will be established; this formulation will then be used to assess zMP-NO.2 efficacy in treating P. aeruginosa in a rabbit in vivo sinusitis model. At the conclusion of this Phase 1 study, an Optimized Test Formulation will be established with a defined concentration of zMP-NO.2 suitable for further formulation development, scale-up, safety studies, and ex vivo efficacy studies in Phase 2.