Key-properties outlook of a levofloxacin-loaded acrylic bone cement with improved antibiotic delivery Ana C. Matos a , Isabel A.C. Ribeiro a , Rita C. Guedes a , Rosana Pinto a , Mário A. Vaz b , Lídia M. Gonçalves a , António J. Almeida a , Ana F. Bettencourt a, * a Research Institute for Medicines (iMed. ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal b INEGI, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, s/n 4200-465 Porto, Portugal A R T I C L E I N F O Article history: Received 6 January 2015 Received in revised form 12 March 2015 Accepted 16 March 2015 Available online 19 March 2015 Keywords: Poly(methylmethacrylate) Fluoroquinolone Staphylococcus-infection Controlled release Density functional theory A B S T R A C T Antibiotic-loaded acrylic bone cements (ALABCs) are widely used to decrease the occurrence of bone infections in cemented arthroplasties and actually being considered as a more cost-effective procedure when compared to cementless implants. However, ALABCs have a major drawback, which is the incomplete release of the antibiotics and, as a result, pathogens that commonly are responsible for those infections are becoming resistant. Consequently, it is of most relevance to find new antibacterial agents to load into BC with an effective mechanism against those microorganisms. This research work intended to load levofloxacin, a fluoroquinolone with anti-staphylococcal activity and adequate penetration into osteoarticular tissues, on lactose-modified commercial bone cement (BC). This modified BC matrix exhibited increased levofloxacin release and delayed Staphylococcus aureus biofilm formation. Further insights on material-drug interaction during BC setting were investigated by density functional theory calculations. The obtained results suggested that favorable covalent and non-covalent interactions could be established between levofloxacin and the BC. Moreover, BC mechanical and biocompatibility properties were maintained. These features justify the potential of levofloxacin-loaded modified-BC as a valuable approach for local antibiotic delivery in bone infections management. ã 2015 Elsevier B.V. All rights reserved. 1. Introduction Bone infections remain a burden as a clinical complication of orthopaedic surgeries. Chemotherapeutic treatment includes the intravenously and oral administration of antibiotics for long periods of time along with local delivery, through the use of antibiotic-loaded acrylic bone cements (ALABCs) (Hendriks et al., 2004; Van de Belt et al., 2001). The advantage of the latter is to maintain a high local drug concentration for an extended period of release without exceeding systemic toxicity. To attain this purpose ALABC has been used in cemented arthroplasties, as a well-established procedure, which, however, presents a major drawback regarding the incom- plete and inadequate kinetic elution of the drug (Jiranek et al., 2006; Lewis 2009; Shi et al., 2010). This fact is related to the structural properties of the non-erodible matrix of the BC, as the hydrophobic- ity and low porosity hamper antibiotic diffusion from the BC core and only the adsorbed antibiotic molecules located in the path of the advancing fluid can dissolve, through voids and cracks, and elute from the matrix (Siepmann et al., 2012). Recent studies favor the use of cemented over cementless implants, as these offer no net advantage while being more costly (Jameson et al., 2015). Therefore, it is important to pursue for improvements in ALABC specially on finding new antibiotics and additives to load and produce matrices able to perform a better antibiotic release, preventing the development of bacterial resistance. This fact has achieved a worldwide concern regarding the danger of reaching the end of antibiotic pipeline, which triggered a growing tendency to preserve novel antibiotics and use alternative compounds with an effective action mechanism against the causative microorganisms (Cooper and Shlaes, 2011; Editorials, 2013). Thereupon, several studies evidence a continued interest in improving the antibacterial activity of fluorinated quinolones on bone infections. Levofloxacin is being referred as the fluoroquino- lone with the greater in vitro, and in vivo, anti-staphylococcal activity and lower toxicity (Giacometti et al., 2003; Holtom et al., 2000; Landersdorfer et al., 2009; Lima et al., 2014; Van Bambeke et al., 2005) besides an adequate penetration into osteoarticular tissues above the minimum inhibitory concentration (MIC) for * Corresponding author at: iMed. ULisboa, Faculty of Pharmacy, University of Lisbon, Portugal. Tel.: +351 21 794 64 00; fax: +351 21 794 64 70. E-mail address: asimao@ff.ulisboa.pt (A.F. Bettencourt). http://dx.doi.org/10.1016/j.ijpharm.2015.03.035 0378-5173/ ã 2015 Elsevier B.V. All rights reserved. International Journal of Pharmaceutics 485 (2015) 317–328 Contents lists available at ScienceDirect International Journal of Pharmaceutics journal homepage: www.elsev ier.com/locate /ijpharm