Efficacy of Tobramycin Conjugated to Superparamagnetic Iron Oxide Nanoparticles in Treating Cystic Fibrosis Infections
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Efficacy of Tobramycin Conjugated to Superparamagnetic Iron Oxide Nanoparticles in Treating Cystic Fibrosis Infections Marek Osiński1, Yekaterina I. Brandt1, Leisha M. Armijo1, Michael Kopciuch1, Nathan. J. Withers1, Nathaniel C. Cook1, Natalie L. Adolphi2, Gennady A. Smolyakov1, and Hugh D. C. Smyth3 1 Center for High Technology Materials, University of New Mexico, 1313 Goddard SE, Albuquerque, NM 87106-4343, U.S.A. Tel. +1 (505) 272-7812; Fax +1 (505) 272-7801; E-mail: [email protected] 2 Department of Biochemistry and Molecular Biology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, U.S.A. 3 College of Pharmacy, University of Texas at Austin, Austin, TX 78712, U.S.A. ABSTRACT Cystic fibrosis (CF) is an inherited childhood-onset life-shortening disease. It is characterized by increased respiratory production, leading to airway obstruction, chronic lung infection and inflammatory reactions. The most common bacteria causing persisting infections in people with CF is Pseudomonas aeruginosa. Superparamagnetic Fe3O4 iron oxide nanoparticles (NPs) conjugated to the antibiotic (tobramycin), guided by a gradient of the magnetic field or subjected to an oscillating magnetic field, show promise in improving the drug delivery across the mucus and P. aeruginosa biofilm to the bacteria. The question remains whether tobramycin needs to be released from the NPs after the penetration of the mucus barrier in order to act upon the pathogenic bacteria. We used a zero-length 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) crosslinking agent to couple tobramycin, via its amine groups, to the carboxyl groups on Fe3O4 NPs capped with citric acid. The therapeutic efficiency of Fe3O4 NPs attached to the drug versus that of the free drug was investigated in P. aeruginosa culture. INTRODUCTION Cystic fibrosis (CF) is a life-shortening debilitating inherited disease, occurring in 1 out of every 3,900 children born in the United States [1]. It currently affects 30,000 people in the Untied States, and 70,000 worldwide [2]. In the 1950s, few children with CF lived long enough to attend elementary school. Today, advances in research and medical treatments have significantly enhanced and extended life expectancy of CF patients. Nonetheless, even with intensive treatment, current median life expectancy is only 36.8 years. The disease is mediated by an autosomal recessive genetic defect, specifically by a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein [3]. CFTR is a membrane-bound glycoprotein, consisting of 1480 amino acids with a molecular mass of 170,000 Da [4]. It is present in the cells of secretory epithelia and exocrine glands, where it functions as a chloride ion channel. The CFTR-mediated influx of Cl ions in the lung can regulate absorption of ions in excess of water, creating hypotonic water outside the cells. In epithelial cells of pancreas and intestine, CFTR regulates water secretion via Cl ion efflux. It also disrupts the functioning of
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