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Antibiotic-coupled magnetic nanoparticles for the treatment of Pseudomonas aeruginosa infections


The major achievements of this work include the synthesis & characterization of iron oxide nanoparticles for application in the treatment of cystic fibrosis lung infections, the leading cause of mortality in cystic fibrosis patients. We investigated the use of magnetic nanoparticles (MNPs) to increase the effectiveness of administering antibiotics through aerosol inhalation using two mechanisms: directed particle movement in the presence of an inhomogeneous static external magnetic field & magnetic hyperthermia.

Magnetic hyperthermia is an effective method for decreasing the viscosity of the mucus & biofilm, thereby enhancing drug, immune cell, & antibody penetration to the affected area. Iron oxide nanoparticles of various sizes & morphologies were synthesized & tested for specific losses (heating power). Nanoparticles in the superparamagnetic to ferromagnetic size range exhibited excellent heating power. Iron III is naturally internalized by many pathogenic bacterial strains, therefore the selection of Fe3O4 as the nanomaterial for drug delivery eliminates the need for ligand-binding & triggered release of the conjugated drug. We report 100% bacterial annihilation with the MNP conjugated drug. Additionally, magnetic hyperthermia will allow biofilm destruction while slowing the growth rate, as the biofilm mode of growth is strongly dependent on physiological temperature.

The ultimate goal of this research is the delivery of antibiotics to bacterial colonies in cystic fibrosis (CF) lungs using SPIONs. CF is one of the most common life-shortening, childhood-onset recessively inherited diseases, affecting 1 in 3,419 Caucasian children. CF is caused by a mutation in the CF transmembrane conductance regulator gene (CFTR) on chromosome 7, resulting in a chloride ion channel malfunction. The malfunction causes a decreased volume of the periciliary fluid in the lower respiratory tract, leading to impaired mucociliary clearance of inhaled opportunistic bacteria, such as Pseudomonas aeruginosa and Burkholderia cepacia complex (Bcc). This failure of the innate mechanical immune system results in a state of chronic inflammation due to the recruitment of polymorphonuclear leukocytes (PMNs) & antibodies. CF patients suffer from chronic respiratory tract infections, characterized by PMN-mediated inflammation, beginning in childhood.

Despite the inflammatory response & antibiotic therapy, infections of P. aeruginosa and Bcc persist & ultimately lead to respiratory failure and death. The mean lifespan of a CF patient today is 32-37 years with intensive treatment. There is a significant gender gap, with the lifespan of female patients being shorter by 2-5 years compared to male patients. P. aeruginosa and Bcc bacteria use adaptive mechanisms to survive, despite the presence of antibiotics & antibodies in their environment. The pathogenic bacteria switch to the biofilm mode of growth, which provides protection from the inflammatory defense mechanism, antibiotic therapy, & adverse environmental conditions, such as low oxygen & nutrient availability. Although inhalation aerosols have made a significant improvement in the life expectancy of CF patients (only 14 years in 1969), the bacterial production of extracellular biofilms has greatly reduced the efficacy of therapeutics due to the inability of the drug to penetrate the biofilm barrier & to reach the target bacterial pathogens. P. aeruginosa is the most common of respiratory pathogens reported in CF patients, with ~61% of all CF cases involving this bacteria. For this reason, our studies have focused on P. aeruginosa.

Since CF sputum is highly viscous, hypoxic conditions exist, which actually promote biofilm formation by P. aeruginosa, consequently resulting in two barriers limiting the ability of inhalation aerosol antibiotics to reach the infection: a viscous mucus layer & a protective biofilm. Previous studies have shown that although micrometer & larger size particles are often entrapped in mucus, small sized particles (120nm) exceeded the rate of diffusion through mucus when compared to larger particles (560nm). These findings are significant, since it is now known that the maximum pore size in CF sputum is 400nm. Therefore, an ideal drug carrier would have to be significantly smaller than 400nm to enhance the rate of free diffusion of the particles through mucus pores. In response to these findings, we have synthesized nanoparticles in the 20-30nm size range.

The physical properties of the biofilm are slightly different from mucus. In general, biofilms are composed of an exopolysaccharide (EPS) layer. The EPS commonly synthesized by P. aeruginosa is the block copolymer of alginate, an anionic polysaccharide. Because the biofilm & mucus layers both contain negatively charged biomolecules such as DNA, polyethylene glycol (PEG) capping increases the rate of free diffusion by shielding the surface charge of the particles & allowing unhindered passage through the media. Diffusion of particles through cervical mucus was enhanced three-fold for PEG-capped particles, when compared to uncapped particles. Despite this, enhancing the rate of free diffusion of the particles alone has not proven sufficient to deliver therapeutic amounts of drug to these biofilm communities. An active transport method is called for. MNPs may be magnetic gradient-guided to the infected area using an external electromagnet. To determine the effect of tobramycin-coupled Fe3O4 NPs on viability of P. aeruginosa, 1mL aliquots of liquid overnight P. aeruginosa cultures grown to the OD600 of 0.5-0.6 were diluted with 1mL of H2O alone (control), or 1mL of H2O containing either re-suspended Fe3O4 NPs, previously subjected to conjugation reaction with tobramycin, or unconjugated Fe3O4 NPs. The cultures were put into a rotating shaker and grown overnight at 37 ÂșC and 150 rpm. A well-mixed aliquot of the overnight culture was diluted 1:2 with TSB and its optical density at 600nm (OD600)

Address Goals

The primary and secondary goals this work addresses are discovery and learning, respectively. These findings reduce the cost of MNP drug delivery by using a nanomaterial which is naturally internalized by the target cells. Having established that the antibiotic drug retains antibacterial effects without triggered drug release will contribute to this field dramatically. While developing these materials, we have emphasized the necessity of green chemistry methods and the production of non-toxic materials for the sake of the patients, our employees, and our environment. Many students have had the opportunity to learn the requirements of these methods as well as employing them in their research. Green chemistry is necessary to ensure safety and the continued success of the nanotechnology age.